Usually called “Chinese Magnolia”, Schizandreae Chinensis has a well recognized history in traditional Chinese medicine. It grows in the Eastern regions of Siberia, China, Japan, and Korea. Its roots, the stem, and its leaves have a strong citric fragrance and therefore in Russia it is known as little lemon tree.
Since ancestral times, Schizandrae is a traditional Chinese medicine and its juice and fruits are used to regain strength. Scientific tests with Schizandrae began in the Soviet Union during the decade of the fourties when they began to use alcoholic extracts of its fruits for clinical investigations.
Its properties as a primary (energizing) adaptogen explain why a range of physical, chemical, and emotional impacts increase, while the regulation of physiological processes is improved. Experimental evidence suggests that Schizandrae has hepatoprotective effects and acts as a strong energizer and antioxidant. |
Press the bottle to see a photo of this plant |
At the beginning of the 70s, it was shown that the fruits of this plant could reduce the high seric glutamatic-piruvic and glutamic-oxalacetic transaminase levels (SGPT - SGOT) in patients who suffer from chronic viral hepatitis.
Recent studies have shown that Schizandrae and its principal active components act against acute and chronic hepatitis, chemical hepatitis, hepatic cirrhosis and degeneration of fat. Furthermore, to reduce hepatic toxity and carcinogenic effects caused by some drugs (like acetaminophen) and toxic substances.
Schizandrae suppresses histological changes like: fibrosis, degeneration of fat, atrophy and cellular necrosis and the infiltration of inflammatory cells. Increases the blood irrigation, the weight of the liver and reduces its contents of triglycerides and lipids. In the case of chronic hepatopathy, it accelerates the regeneration and recovery of hepatic functions.
The administration of Schizandrae normalizes the hepatic enzymes in 72% of all cases after an average of 25 days and without any adverse secondary effects. Presently, it is widely used to improve hepatic functions in patients with acute and chronic hepatopathies and as hepatic protection with patients who are under chemotherapeutic treatment against neoplasic sicknesses, without causing any secondary effects.
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Active Components:
The first extracted active component with adaptogenic properties was isolated in 1951 and its molecular structure was identified as a lignane with an skeleton of dibenzocyclooctadine (Schizandrine B) in 1962.
During the last 20 years there have been other Schinzadrines isolated, called by the Japanese “Gomisins: A (TJN-101), B (dibenzocyclooctadine), C (dimethyl-diphenyl-bicarboxilate DDB), D, E, F, G, N and J.
Schizandol A and B.
Schizandrer A and B.
Schizanhenol.
Deoxischizandrine, sesquicarene, citral.
ß-Chamigrene, stigmaster and vitamins C and E. |
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Mechanism of Action:
1. Adaptogenic Action
- Energizing:
Increases the activity of some enzymes that interfere in the oxidizing phosphorilation. Reduces tiredness and increases the resistance to exercises.
- Stimulates the Nervous System:
Various studies have shown that the lignanes of Schizandrae act as modulators of the catecolaminergic synopsis function. Improves the capacity of concentration.
- Oxygenator:
Improves the oxygen supply to muscles, brain and liver during physical exercises.
- Immune-modulator:
Some of its schizandrines antagonize the platelet activating factor and therefore act as modulators for immune responses.
Tests with children and adults show a reduction of 43% of flu incidents.
- Anti-oxidant:
Some schizandrines have a strong antioxidant response as they scavenge free radicals of oxygen. Increases the activity of superoxid dismutase and catalase. Its antioxidant effect is higher than the one of vitamins E and C.
- Others:
Inhibits the development of pre-malign damages of liver and skin.
Improves the view at night and accelerates the capacity of adaption to darkness.
Good treatment for excessive nightly sweating.
- Action on the Cardiovascular System:
Anti-arrhythmic, cardiotonic and hypertensive effect.
Reduces the hyperlipemia and inhibits significantly the development of arteriosclerosis.
- Action on the Genital-Urinary System:
Nefrotonic effect. Improves the insipid diabetes.
Treatment of erectile dysfunction and of premature ejaculation. Aphrodisiac and treatment of male infertility.
2. Hepatic Protector
- Maintains the integrity of the cellular and hepatocic membranes.
- Increases the hepatic levels of ascorbic acid (vitamin C).
- Inhibits NADPH oxidizing, increasing the NADPH-cytochrome and reductase.
- Inhibits the lipid peroxydizing at hepatic microsome level and the formation of hepatic malondialdehyde.
- Reduces the production of carbon monoxide at hepatic level.
- These mechanisms explain its important antioxidant action which protects against hepatoxic agents.
- Induces effect on the microsome hepatic cytochrome P-450 enzymatic system, which contributes to the explanation of its anti-toxic, anti-carcinogenic, and anti-mutagenic actions.
- Prevents the cholestasis induced by toxic substances, increasing the bile flow and the evacuation of toxic substances by the bile.
3. Hepatic Stabilizer:
- Reduces the plasmatic levels of transaminases and improves the recovery of hepatic functions, which indicates a reduction of the hepatic-cellular damage.
4. Hepatic Regeneration:
- Induces the formation of mRNA for the growth factor of the hepatocyte (FCH) which contributes to its regeneration.
- Stimulates the profileration of the flat endoplasmic reticulum of the hepacyte and accelerates the proliferation of hepatocytes.
- Increases the activity of the ornithine decarboxilase, the mitotic index, and facilitates the synthesis of AND and hepatic proteins, stimulating the regeneration of this organ.
- Increases the levels of mitochondrial hepatic glutation and the activity of the mitochondrial reductase glutation and the hepatic glucose-6-phosphate, improving the capacity of regeneration of the reduced glutation and the synthesis of hepatic glucogen.
- Increases the blood flow to the liver.
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SYSTEMIC MEDICINE AND SCHIZANDRA CHINENSIS
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Dosage and Toxity:
The therapeutic dosage is 400 - 500 mg, twice per day.
Observations:
At the initial stage of the treatment with schizandrae an increase of the hepatic size may be observed, due to the increase of the blood flow to the liver and an adaptative hypotrophy, due to an enzymatic induction.
Medicamental Interaction:
Reduces the seric levels of cyclosporine A en the case of a renal transplant.
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| Contraindications:
Not recommended for patients with convulsive syndromes or who recently have suffered a cerebrovascular accident.
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References
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Mol Cell Biochem. 2004 Nov;266(1-2):139-44.
Schisandrin B protects myocardial ischemia-reperfusion injury partly by inducing Hsp25 and Hsp70 expression in rats.
Chiu PY, Ko KM. Department of Biochemistry, The Hong Kong University of Science & Technology, Hong Kong SAR, China. |
| Schisandrin B (Sch B) is a hepato- and cardioprotective ingredient isolated from the fruit of Schisandra chinensis, a traditional Chinese herb clinically used to treat viral and chemical hepatitis. In order to investigate whether the induction of heat shock protein (Hsp)25 and Hsp70 expression plays a role in the cardioprotection afforded by Sch B pre-treatment against ischemia-reperfusion (I-R) injury, the time-course of myocardial Hsp25 and Hsp70 expression was examined in Sch B-pre-treated rats. Sch B pre-treatment (1.2 mmol/kg) produced time-dependent increases in Hsp25 and Hsp70 expression in rat hearts, with the maximum enhancement observable at 48 and 72 h post-dosing, respectively. Buthionine sulfoximine/phorone treatment, while abolishing the beneficial effect of Sch B on mitochondrial glutathione redox status, did not completely abrogate the cardioprotection against I-R injury. Heat shock treatment could increase myocardial Hsp25 and Hsp70 expression and protect against I-R injury under the present experimental conditions. The results indicate that the induction of Hsp25 and Hsp70 expression contributes at least partly to the cardioprotection afforded by Sch B pre-treatment against I-R injury. |
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2: Drug Metab Dispos. 2004 Dec;32(12):1351-8
Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract.
Iwata H, Tezuka Y, Kadota S. Division of Natural Products Chemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan. |
| Schisandra fruit, a Schisandraceae family herb, is used as a component in Kampo medicines (developed from Chinese medicines, but established in Japan). It can act as a sedative and antitussive, improve hepatic function, and give a general tonic effect. An extract of Schisandra fruit has been shown with a potent inhibitory effect on human liver microsomal erythromycin N-demethylation activity mediated by cytochrome P450 3A4 (CYP3A4). The present study was conducted to identify Schisandra fruit components having inhibitory effects on CYP3A4 by surveying the effect on human liver microsomal erythromycin N-demethylation activity. Known components of Schisandra fruit, gomisins B, C, G, and N and gamma-shizandrin, showed inhibitory effects on N-demethylation activity. Among these components, gomisin C displayed the most potent and competitive inhibitory effect, with a Ki value of 0.049 microM. Furthermore, the inhibitory effect of gomisin C was stronger than that of ketoconazole (Ki = 0.070 microM), a known potent CYP3A4 inhibitor. Gomisin C, however, inhibited CYP1A2-, CYP2C9-, CYP2C19-, and CYP2D6-dependent activities only to a limited extent (IC50 values >10 microM). Moreover, gomisin C inactivated human liver microsomal erythromycin N-demethylation activity in a time- and concentration-dependent manner. The inactivation kinetic parameters k(inact) and K(I) were 0.092 min(-1) and 0.399 microM, respectively. The human liver microsomal erythromycin N-demethylation activity inactivated by gomisin C did not recover on dialysis of the microsomes. Spectral scanning of CYP3A4 with gomisin C yielded an absorbance at 455 nm, suggesting that gomisin C inactivated the cytochrome P450 via the formation of a metabolite intermediate complex. This pattern is consistent with the metabolism of the methylenedioxy substituent in gomisin C. These results indicate that gomisin C is a mechanism-based inhibitor that not only competitively inhibits but irreversibly inactivates CYP3A4. |
3: Zhong Yao Cai. 2004 Mar;27(3):202-3.
Pathological observations of Fructus Schisandrae polysaccharide on anti-tumor effects in S180-bearing mice
Huang L, Chen L, Zhang Z. Fujian College of Traditional Chinese Medicine, Fuzhou 350003.
OBJECTIVE: To study the effects of Fructus Schisandrae Polysaccharide (FSP) on anti-tumor in S180-bearing mice. METHODS: The transplantable carcinosarcoma model was established in S180-bearing mice by subcutaneous implantation. Tumor size and histopathological changes were observed under electron microscopy by HE staining after 8 days treatment. RESULTS: Morphological changes showed that slight cataplasia and apoptosis were induced by high concentration FSP, as well as the numbers of inflammatory cells in tumor were increased and tumor cells in infiltration areas around tumor cataplasised partly. These suggested that high concentration FSP can inhibit tumor growth lightly. In addition, high concentration FSP combined with cyclophosphamide can promote the effect of anti-tumor. CONCLUSIONS: FSP can inhibit tumor growth, this effect may be correlated with apoptosis and the activation of immunocytes, but not depend on killing tumor cells directly. In addition, high concentration FSP combined with cyclophosphamide can promote the capacity on anti-tumor in S180-bearing mice. |
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4: J Neurosci Res. 2004 May 1;76(3):397-405.
Dibenzocyclooctadiene lignans from Schisandra chinensis protect primary cultures of rat cortical cells from glutamate-induced toxicity.
Kim SR, Lee MK, Koo KA. College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul, Korea. |
| A methanolic extract of dried Schisandra fruit (Schisandra chinensis Baill.; Schisandraceae) significantly attenuated the neurotoxicity induced by L-glutamate in primary cultures of rat cortical cells. Five dibenzocyclooctadiene lignans (deoxyschisandrin, gomisin N, gomisin A, schisandrin, and wuweizisu C) were isolated from the methanolic extract; their protective effects against glutamate-induced neurotoxicity were then evaluated. Among the five lignans, deoxyschisandrin, gomisin N, and wuweizisu C significantly attenuated glutamate-induced neurotoxicity as measured by 1). an inhibition in the increase of intracellular [Ca(2+)]; 2). an improvement in the glutathione defense system, the level of glutathione, and the activity of glutathione peroxidase; and 3). an inhibition in the formation of cellular peroxide. These results suggest that dibenzocyclooctadiene lignans from Schisandra chinensis may possess therapeutic potential against oxidative neuronal damage induced by excitotoxin. Copyright 2004 Wiley-Liss, Inc. |
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5: J Lipid Res. 2004 Jun;45(6):1092-103.
Natural occurrence of cancer-preventive geranylgeranoic acid in medicinal herbs.
Shidoji Y, Ogawa H. Laboratory of Cellular Biochemistry, Graduate School of Human Health Sciences, Siebold University of Nagasaki, Nagayo, Nagasaki, Japan.
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| Geranylgeranoic acid (GGA; all-trans 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid) has been shown to induce apoptosis in a human hepatoma-derived cell line, HuH-7. We aimed not only to confirm the apoptogenic properties of GGA and its derivatives, but also to search for natural GGA in medicinal herbs. GGA induced apoptosis in human hepatoma-derived cell lines, HuH-7, PLC/PRF-5, and mouse transformed hepatocyte-derived cell line, MLE-10, in a dose- and time-dependent manner, but failed to induce cell death in human hepatoblastoma-derived HepG-2 and mouse primary hepatocytes in the same condition. Besides GGA, 4,5-didehydro GGA, 14,15-dihydro GGA, and 2,3-dihydro GGA were also active to induce cell death in HuH-7 cells, while 4,5-didehydro-10,11, 14,15-tetrahydro GGA, 4,5,8,9-tetrahydro GGA, farnesoic acid, and geranylgeraniol were inert. By using liquid chromatography/mass spectrometry, we found natural GGA as a negative ion of m/z 303.4 in a Chinese herb, Schisandra chinensis, and Schisandra GGA was identified by derivatization with both mild methylation and catalytic hydrogenation. Some other GGAs hydrogenated in the different degrees, including phytanic acid (perhydro GGA), were also found in S. chinensis. GGA and phytanic acid were detected in 24 out of 25 herbs tested. The present study is the first report of natural GGA in medicinal herbs. |
6: Biosci Biotechnol Biochem. 2003 Aug;67(8):1629-35.
Small scale rat hepatocyte primary culture with applications for screening hepatoprotective substances.
Nakagiri R. Kyowa Hakko Kogyo Co., Ltd., Tsukuba Research Laboratories, 2 Miyukigaoka, Tsukuba-shi, Ibaraki 305-0841, Japan .
Isolated hepatocytes are known to maintain their physiological functions for over a week when cultured on Matrigel, artificially reconstituted from basement membrane components. Although this culture technique has been frequently used in research on hepatocyte functions, there has been a limitation on its application for small scale experiments due to some technical problems. By using micro-culture plates with 96 round-bottom wells, we succeeded in coating the wells uniformly with Matrigel. When the cultured hepatocytes were treated with either 10 mM, 15 mM, or 20 mM of acetaminophen or 1 mM, 10 mM, or 20 mM of D-galactosamine, the viability of the hepatocytes became 91.1%, 75.3%, 64.7%, and 79.0%, 43.8%, 26.2% of the non-treated control at 48 hours, respectively. Fractionated extracts of Glycyrrhiza glabra L. and Schisandra chinensis Baillon inhibited the action of acetaminophen or D-galactosamine in this model. From these results, we concluded that the microculture system presented here is capable of maintaining the in vivo characteristics of hepatocytes and is suitable for the screening of hepatoprotective substances. |
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7: Pigment Cell Res. 2003 Oct;16(5):494-500.
Down-regulation of melanin synthesis by a biphenyl derivative and its mechanism.
Nakamura K, Yoshida M, Uchiwa H. Basic Research Laboratory, Kanebo Ltd., Kanagawa , Japan
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| Down-regulation of melanin synthesis is required for recovery of pigmentary disorders and it is known that direct inhibitors of tyrosinase, the key enzyme in melanin synthesis, such as hydroquinone with a phenol structure, suppress melanin synthesis. We screened several phenolic derivatives using B16 melanoma cells and found that a biphenyl derivative, 2,2'-dihydroxy-5,5'-dipropyl-biphenyl (DDB), down-regulated melanin synthesis effectively. Although DDB has a phenol structure, it did not inhibit tyrosinase in vitro, thus we examined its mechanism in detail. Western blotting revealed that the amount of tyrosinase was decreased by DDB, and pulse-chase labeling and immunoprecipitation analysis showed a decrease of mature tyrosinase and acceleration of tyrosinase degradation in its presence. These results suggest that DDB down-regulates melanin synthesis by inhibiting the maturation of tyrosinase, leading to acceleration of tyrosinase degradation. |
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8: Free Radic Biol Med. 2003 Aug 15;35(4):368-80.
Hepatoprotective mechanism of schisandrin B: role of mitochondrial glutathione antioxidant status and heat shock proteins.
Chiu PY. Department of Biochemistry, The Hong Kong University of Science and Technology, Hong Kong , China . |
| In this study, the time course of schisandrin B- (Sch B-) induced changes in hepatic mitochondrial glutathione antioxidant status (mtGAS) and heat shock protein (HSP) 25/70 induction was examined to study their differential roles in the hepatoprotection afforded by Sch B pretreatment against carbon tetrachloride (CCl(4)) toxicity in mice. Dimethyl diphenyl bicarboxylate (DDB), a nonhepatoprotective analog of Sch B, was also included for comparison. The results indicate that Sch B treatment (2 mmol/kg) produced maximum enhancement in hepatic mtGAS and increases in both hepatic HSP 25 and HSP 70 levels at 24 h after dosing. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl(4) was found to correlate inversely with the elapsed time postdosing, the protective effect was associated with the ability to sustain mtGAS and/or HSP 70 levels in a CCl(4)-intoxicated condition. On the other hand, DDB (2 mmol/kg) treatment, which did not sustain mtGAS and HSP 70 level, could not protect against CCl(4) toxicity. Abolition of the Sch B-mediated enhancement of mtGAS by buthionine sulfoximine/phorone did not completely abrogate the hepatoprotective action of Sch B. The results indicate that Sch B pretreatment independently enhances mtGAS and induces HSP 25/70 production, particularly under conditions of oxidative stress, thereby protecting against CCl(4) hepatotoxicity. |
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9: Phytomedicine. 2003 May;10(4):271-85.
Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever.
Amaryan G, Astvatsatryan V, Gabrielyan E. Republican Children's FMF Center, Yerevan State Medical University, Yerevan, Armenia. |
Double blind, randomized, placebo controlled pilot study of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees., Eleutherococcus senticosus Maxim., Schizandra chinensis Bail., and Glycyrrhiza glabra L. special extracts standardized for the content of Andrographolide (4 mg/tablet), Eleuteroside E, Schisandrins and Glycyrrhizin, was carried out in two parallel groups of patients. The study was conducted in 24 (3-15 years of both genders) patients with Familial Mediterranean Fever (FMF), 14 were treated with tablets of series A (verum) and 10 patients received series B product (placebo). The study medication was taken three times of four tablets daily for 1 month. Daily dose of the andrographolide--48 mg. The primary outcome measures in physician's evaluation were related to duration, frequency and severity of attacks in FMF patients (attacks characteristics score). The patient's self-evaluation was based mainly on symptoms--abdominal, chest pains, temperature, arthritis, myalgia, erysipelas-like erythema. All of 3 features (duration, frequency, severity of attacks) showed significant improvement in the verum group as compared with the placebo. In both clinical and self evaluation the severity of attacks was found to show the most significant improvement in the verum group. Both the clinical and laboratory results of the present phase II (pilot) clinical study suggest that ImmunoGuard is a safe and efficacious herbal drug for the management of patients with FMF.
Publication Types:
• Clinical Trial
• Randomized Controlled Trial |
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10: Phytochem Anal. 2003 Jan-Feb;14(1):23-33.
Analysis of volatile fractions of Schisandra chinensis (Turcz.) Baill. using GC-MS and chemometric resolution.
Li XN. College of Chemistry and Chemical Engineering, Institute of Chemometrics and Chemical Sensing Technology, Hunan University , People's Republic of China . |
| The two-dimensional data obtained from GC-MS has been used qualitatively and quantitatively to determine the components of the volatile fractions of Schisandra chinensis obtained by six different extraction methods. Sub-window factor analysis (SFA) was employed to confirm the identities of components determined in different samples. With the help of SFA, and other chemometric techniques, peak purity in the chromatograms was determined, and overlapping peaks were resolved to yield a pure chromatographic profile and mass spectrum for each component. It is demonstrated that the accuracy of qualitative and quantitative analysis may be greatly enhanced using chemometric resolution methods, such methods being particularly valuable with respect to the analysis of complex samples such as traditional Chinese medicines. It is further demonstrated that different extraction methods give rise to volatile fractions of S. chinensis which differ qualitatively and quantitatively in their composition. |
11: Yao Xue Xue Bao. 2001 Jul;36(7):493-7.
[Effect of dimethyl diphenyl bicarboxylate (DDB) on 9-amino-1,2,3,4-tetrahydroacridine-induced hepatotoxicity in mice]
Li Y. Institute of Materia Medica, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100050, China.
AIM: To establish an acute model of THA-induced hepatotoxicity in mice, and observe the effects of DDB on THA-induced liver damage. METHODS: After a single oral dose of THA (56 mg.kg-1), body temperatures, liver MDA content and serum ALT were measured within 12 h. The activities of mice brain acetylcholinesterase, liver microsomal 7-ethoxyresorufin deethylase, uridine-5'-diphosphoglucuronic transferase, and mitochondria potential change were also observed. RESULTS: The alteration of mice body temperature, and the elevation of serum ALT, liver MDA content, and mitochondria potential induced by THA were significantly inhibited by DDB pretreatment. The microsomal 7-ethoxyresorufin deethylase activity was induced by DDB too. On the other hand, The inhibiting effects of THA on mice hippocampus and cortex acetylcholinesterase in vitro and in vivo were not influenced by DDB treatment. CONCLUSION: The toxic effect of THA on mice liver was significantly reduced by DDB. These results demonstrate that the protective action of DDB may attribute to its regulation on enzymes involved in THA metabolism, and its protective effect against mitochondria injury caused by THA. Therefore, DDB may be a potential liverprotector against THA-induced hepatotoxicity during dementia therapy.
12: Yao Xue Xue Bao. 2001 Mar;36(3):215-9.
[Analysis of the essential oil of Schisandra chinensis (Turcz.) Baill. with GC/MS]
Li XN, Cui H, Song YQ. College of Chemistry and Chemical Engineering, Institute of Chemometrics and Chemical Sensing Technology, Hunan University , Changsha , China .
AIM: To detect chemical components of the essential oil of Schisandra chinensis (Turcz.) Baill.. METHODS: The essential oil was analyzed with GC/MS, heuristic evolving latent projections(HELP) resolution and overall volume integration method. RESULTS: HELP method along with the data from GC/MS can be used to conduct the peak purity examination and resolution of overlapping peaks to obtain pure chromatogram and MS spectrum of each component. Fifty six components were separated and 49 of them were qualitatively and quantitatively analyzed. All the components represent about 98.27% of the total content. CONCLUSION: The resolved pure chromatogram and MS spectrum can greatly enhance the reliability of similar searches in the commercial MS database and thus contribute to the accuracy of the qualitative and quantitative analysis of the essential oil.
13: Yao Xue Xue Bao. 2002 Oct;37(10):753-7.
Effects of dimethyl diphenyl bicarboxylate on the metabolism and hepatotoxicity of aflatoxin B1 in rats.
Lu H. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
AIM: To study the effect of antihepatitis drug, dimethyl diphenyl bicarboxylate (DDB) on the metabolism and hepatotoxicity of aflatoxin B1(AFB1) in rats. METHODS: Rats were given orally DDB 300 mg.kg-1.d-1 for 3 days and then injected intraperitioneally with AFB1 1.5 mg.kg-1. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were examined 16 hours after the injection of AFB1. The in vitro metabolism of AFB1 by DDB-pretreated rat liver microsome was investigated by HPLC assay. RESULTS: DDB (300 mg.kg-1) pretreatment provided significant protection against AFB1 hepatotoxicity as evidenced by the decrease of AFB1-elevated serum marker enzymes in rats. Pretreatment with DDB was shown to slightly increase the level of AFM1, the less toxic metabolite. DDB significantly increased the liver cytochrome P450 content, P450 isozyme 2B1-mediated 7-pentoxyresorufin O-dealkylase (PROD) activity, cytosolic glutahione (GSH) level and GSH S-transferase (GST) activities. In addition, DDB slightly increased P450 isozymes, 3A-mediated erythromycin-demethylase and 1A-mediated 7-ethoxyresorufin O-deethylase (EROD) activities. CONCLUSION: The results indicate that DDB protected rats against AFB1 hepatotoxicity by increasing the detoxifying metabolism of AFB1 in the liver. |
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14: Planta Med. 2003 Jan;69(1):63-4.
Lignans with inhibitory activity against NFAT transcription from Schisandra chinensis.
Lee IS, Lee HK, Dat NT , Lee MS, Kim JW, Na DS, Kim YH.
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Seven lignans from Schisandra chinensis were investigated for their inhibitory activity on NFAT transcription. Both gomisin N (IC 50 : 1.33 +/- 0.05 microM) and schisandrol A (IC 50 : 1.34 +/- 0.05 microM) showed higher activity than gomisin E (IC 50 : 4.73 +/- 0.09 microM), schisandrin A (IC 50 : 7.23 +/- 0.21 microM), schisandrin C (IC 50 : 7.54 +/- 0.22 microM), benzoylisogomisin O (IC 50 : 11.06 +/- 1.02 microM) and schisandrol B (IC 50 : 16.37 +/- 1.00 microM).
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• Letter |
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15: Planta Med. 2002 Nov;68(11):951-6.
In vivo antioxidant action of a lignan-enriched extract of Schisandra fruit and an anthraquinone-containing extract of Polygonum root in comparison with schisandrin B and emodin.
Chiu PY, Mak DH, Poon MK. Department of Biochemistry, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
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| The in vivo antioxidant action of a lignan-enriched extract of the fruit of Schisandra chinensis (FS) and an anthraquinone-containing extract of the root of Polygonum multiflorum (PME) was compared with their respective active constituents schisandrin B (Sch B) and emodin by examining their effect on hepatic mitochondrial glutathione antioxidant status in control and carbon tetrachloride (CCl 4 )-intoxicated mice. FS and PME pretreatments produced a dose-dependent protection against CCl 4 hepatotoxicity, with the effect of FS being more potent. Pretreatment with Sch B, emodin or alpha-tocopherol (alpha-Toc) also protected against CCl 4 hepatotoxicity, with the effect of Sch B being more potent. The extent of hepatoprotection afforded by FS/Sch B and PME/emodin pretreatment against CCl 4 toxicity was found to correlate well with the degree of enhancement in hepatic mitochondrial glutathione antioxidant status, as evidenced by increases in reduced glutathione level and activities of glutathione reductase, glutathione peroxidase as well as glutathione S-transferases, in both control and CCl 4 -intoxicated mice. alpha-Toc, which did not enhance mitochondrial glutathione antioxidant status, seemed to be less potent in protecting against CCl 4 hepatotoxicity. The ensemble of results indicates that FS/PME produced a more potent in vivo antioxidant action than alpha-Toc by virtue of their ability to enhance hepatic mitochondrial glutathione antioxidant status and that the differential potency of FS and PME can be attributed to the difference in in vivo antioxidant potential between Sch B and emodin. Abbreviations. ALT:alanine aminotransferases CCl 4 :carbon tetrachloride FS:lignan-enriched extract of Schisandra fruit GRD:glutathione reductase GSH:reduced glutathione GSH-Px: Se-glutathione peroxidase GST:glutathione S-transferases mt:mitochondrial MDA:malondialdehyde PME:anthraquinone-containing fraction of Polygonum root Sch B:schisandrin B SDH:sorbitol dehydrogenase alpha-Toc:alpha-tocopherol |
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16: Arch Pharm Res. 2002 Oct;25(5):655-63.
The anti-fibrogenic effect of a pharmaceutical composition of [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] (oltipraz) and dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB).
Kang KW, Kim YG, Kim CW. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Korea . |
| Liver fibrosis is a prepathological state wherein damaged liver tissues in chronic liver diseases, such as hepatitis, are not repaired to normal tissues, but converted to fibrous tissue. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a cancer chemopreventive agent, is effective against a wide variety of chemical carcinogens. Recently, we reported that oltipraz inhibits liver fibrogenesis (Kang et al., 2002). In the present study, the effects of oltipraz in combination with dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) on dimethylnitrosamine (DMN)-induced liver fibrogenesis were assessed in rats. Oltipraz (30 mg/kg body weight, p.o., 3 times per week for 4 weeks) was found to inhibit the increases in plasma ALT, AST and bilirubin by DMN, whereas DDB (30 mg/kg body weight, p.o., 3 times per week for 4 weeks) attenuated the increases in the plasma ALT and bilirubin. The lowered plasma protein and albumin contents in DMN-treated rats were completely restored by oltipraz, but not by DDB. DDB decreases liver cell injury and inflammation through inhibition of nuclear factor-kB. DMN increased the accumulation of liver collagen, as indicated by the increase in the 4-hydroxyproline content in liver homogenates, which was reduced by treatment with oltipraz, but not by DDB. Given the differential effect between oltipraz and DDB, the potential enhancement of antifibrotic efficacy by the drugs was assessed in the animal model. Despite the minimal effect of DDB on DMN-induced fibrogenesis, DDB (5-25 mg/kg), administered together with oltipraz (25-5 mg/kg), showed an additive protective effect against hepatotoxicity and fibrosis induced by DMN, which was shown by the blood chemistry parameters and histopathological analysis. The adequate composition ratio of oltipraz to DDB was 5:1. These results provide information on the pharmaceutical composition, comprising of oltipraz and DDB as the active components, for the treatment and/or prevention of liver fibrosis and cirrhosis. |
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17: Mol Cell Biochem. 2002 Sep;238(1-2):181-6.
Schisandrin B protects against tert-butylhydroperoxide induced cerebral toxicity by enhancing glutathione antioxidant status in mouse brain.
Ko KM. Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay , China .
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| Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from Fructus Schisandrae, has been shown to produce antioxidant effect on rodent liver and heart. A mouse model of tert-butylhydroperoxide (t-BHP) induced cerebral toxicity was adopted for examining the antioxidant potential of Sch B in the brain. Intracerebroventricular injection of t-BHP caused a time-dependent increase in mortality rate in mice. The t-BHP toxicity was associated with an increase in the extent of cerebral lipid peroxidation and an impairment in cerebral glutathione antioxidant status, as evidenced by the abrupt decrease in reduced glutathione (GSH) level and the inhibition of Se-glutathione peroxidase activity at 5 min following t-BHP challenge. Sch B pretreatment (1 or 2 mmol/kg/day x 3) produced a dose-dependent protection against t-BHP induced mortality. The protection was associated with a decrease in the extent of lipid peroxidation and an enhancement in glutathione antioxidant status in brain tissue detectable at 5 min post t-BHP challenge, with the assessed biochemical parameters being returned to normal values at 60 min in Sch B pretreated mice at a dose of 2 mmol/kg. The ensemble of results suggests the antioxidant potential of Sch B pretreatment in protecting against cerebral oxidative stress. |
18: Yao Xue Xue Bao. 1998 Jun;33(6):424-8.
[Total synthesis of schizandrin, the main active ingredient isolated from the Chinese herbal medicine fructus schizandrae]
Chang J, Xie J. Henan Institute of Chemistry, Zhengzhou 450003.
In this paper, schizandrin(9), the main active ingredient isolated from Schisandra chinensis, was synthesized from gallic acid by a new route. This route consists of only nine steps, including reductive-coupling reaction of compound(5) and dehydryoxylatic reaction of compound(6) to give compounds(7Z, 7E). By hydroboration, compound (8) was obtained from compound(7Z). With the presence of thallium trifluoroacetate (TTFA) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) compound (9) is obtained from compound (8) by intramolecular nonphenolic oxidative coupling. These compounds were identified by elemental analysis, MS, UV, IR and NMR spectra. |
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19: J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Apr 25;770(1-2):283-9.
Liquid chromatographic analysis of supercritical carbon dioxide extracts of Schizandra chinensis.
Bartlova M , Opletal L, Chobot V. Institute of Chemical Process Fundamentals, Academy of Sciences of the Czech Republic, Prague.
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| Six major lignans (schizandrin, gomisin A, deoxyschizandrin, y-schizandrin, gomisin N, wuweizisu C) in the caulomas and leaves of Schizandra chinensis (Turcz.) Baill., and cinnamic acid in the leaves of the plant, were quantitatively analysed by high-performance liquid chromatography in reversed-phase mode with UV detection. Resolution of the determined lignans was evaluated for two multistep gradients applied. Samples for HPLC analysis were prepared by extraction with supercritical carbon dioxide at pressures of 20-27 MPa and temperatures of 40-60 degrees C. Kinetics of the extraction of individual components was measured and simulated with a model. |
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20: Planta Med. 2002 Mar;68(3):217-20.
Schisandrin B protects against tacrine- and bis(7)-tacrine-induced hepatotoxicity and enhances cognitive function in mice.
Pan SY, Han YF, Carlier PR. Department of Biochemistry, Hong Kong University of Science & Technology, China. |
| Intragastric administration (100-200 micromol/kg) of tacrine (THA) or bis(7)-THA could cause an acute and dose-dependent increase in plasma alanine aminotransferases activity in mice at 6 h after the drug administration. The increase in plasma enzyme activity was associated with an increase in hepatic malondialdehyde level, an indirect index of oxidative tissue damage. Pretreating mice with schisandrin B (Sch B), an active dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, at a daily dose of 0.125-0.5 mmol/kg for 3 days protected against the THA/bis(7)-THA induced hepatic oxidative damage in a dose-dependent manner. Sch B treatment (0.025-0.5 mmol/kg/day x 5) also enhanced the passive avoidance-response in mice as assessed by the step-through task experiment. The ensemble of results suggests that Sch B may be useful for reducing the potential hepatotoxicity of THA/bis(7)-THA in anti-Alzheimer's therapy. |
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21: Electrophoresis. 2002 Jan;23(2):253-8.
Determination of lignans in Schisandra chinensis using micellar electrokinetic capillary chromatography.
Sterbova H, Sevcikova P, Kvasnickova L. Department of Biochemistry, Faculty of Medicine, Masaryk University, Brno, Czech Republic. |
| Micellar electrokinetic capillary chromatography (MEKC) has been developed as a promising method for the determination of lignans in plant samples. The separation conditions have been optimized with respect to the different parameters including sodium dodecyl sulfate (SDS) and acetonitrile concentration, pH of the background electrolyte, separation voltage, and capillary temperature. The background electrolyte consisting of 40 mM SDS and 35% acetonitrile in 10 mM tetraborate buffer (pH 9.3) was found to be the most suitable electrolyte for this analysis. The applied voltage of 28 kV (positive polarity) and the capillary temperature 25 degrees C gave the best separation of lignans. The interday reproducibility of the peak areas and the migration times was below 2.0%. The results of MEKC analyses were compared with those obtained by capillary electrochromatography (CEC) and reversed-phase high-performance liquid chromatography (RP-HPLC). The possibilities of using this method for the determination of lignans in drug and in serum samples were also tested. |
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22: Drug Metab Dispos. 2001 Dec;29(12):1555-60.
Characterization of the selectivity and mechanism of cytochrome P450 inhibition by dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate.
Kim JY. Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Chungryang, Seoul , Korea . |
| In vitro studies with human liver microsomes and cytochrome P450 (P450) prototype substrates were performed to characterize the selectivity and mechanism of inhibition of P450 by dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB). DDB was found to be a strong inhibitor of testosterone 6beta-hydroxylation activity (CYP3A4) with a K(i) value of 0.27 +/- 0.21 microM. At higher concentrations, DDB marginally inhibited caffeine N(3)-demethylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), and dextromethorphan O-demethylation (CYP2D6) activities, but this compound had no effect on CYP2A6-, CYP2C19-, and CYP2E1-mediated reactions. Spectral analysis indicated that the formation of metabolite-P450 complex having absorbance at 456 nm was concentration-dependent; 5 to 33% of the total P450 was complexed in rat and human liver microsomes after a 5-min incubation with DDB. In addition, microsomal incubations with DDB in the presence of NADPH resulted in a loss of spectral P450 content, which was restored after adding K(3)Fe(CN)(6). This complex formation resulted in a time-dependent loss of CYP3A-catalyzed marker activity (testosterone 6beta-hydroxylation) in human liver microsomes. The inhibition was only partially restored upon dialysis. These results collectively suggest that formation of a metabolite-CYP3A complex with DDB was responsible for the CYP3A-selective time-dependent loss of catalytic function of CYP3A. |
23: Ceska Slov Farm. 2001 Sep;50(5):219-24.
[Phytotherapeutic aspects of diseases of the circulatory system. 8. Chinese magnolia (Schisandra chinensis (Turcz.) Baill.): production of the drugs and their evaluation, therapeutic and dietary preparations]
Opletal L, Krenkova M, Havlickova P.
Katedra farmaceuticke botaniky a ekologie Farmaceuticke fakulty Univerzity Karlovy, Hradec Kralove.
Extracts from the fruits (seeds) of Schisandra chinensis L. and pure isolated substances are one of the components of medicinal preparations designed for the treatment of cardiovascular diseases, liver diseases, diseases of the CNS related to the old age, as a supplement in the treatment of neoplasms, diabetes, etc. They are also used for the production of nutraceuticals (soft drinks and health foods), preparations for oral hygiene and for the care for the skin and hair. The review discusses complex analytical methods used for the determination of the content of substances and the phenomena of population ecology in relation with drug production.
24: Ceska Slov Farm. 2001 Jul;50(4):173-80.
[Phytotherapeutic aspects of diseases of the circulatory system. 7. Schisandra chinensis (Turcz.) Baill.): its composition and biological activity]
Opletal L. Katedra farmaceuticke botaniky a ekologie, Farmaceuticke fakulty, Univerzity Karlovy, Hradec Kralove .
Schisandra chinensis (TURCZ.) BAILL., originally a Japanese-Manchurian endemite, yields a vegetable drug (Schisandrae fructus) with a number of very utilizable therapeutic effects. The paper reports the results of phytochemical and pharmacological-toxicological studies approximately from the year 1990 carried out both with the drug and, in particular, the principal isolated lignans of the dibenzo[a,c]cyclooctadiene type. The results confirm the validity of the historical use of the drug, in particular as a hepatoprotective, adaptogenic, and antioxidative agent. It is obvious that a very positive therapeutic effect based on the use of a complex mixture of its principal constituents because their biological effects are complementary and potentiate each other. At the same time, some lignans (e.g. gomisin A, gomisin N) are interesting as new prospective medicines.
Publication Types:
• Review
• Review, Academic |
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25: J Chromatogr A. 2001 May 4;916(1-2):265-71.
Application of capillary electrochromatography using macroporous polyacrylamide columns for the analysis of lignans from seeds of Schisandra chinensis.
Kvasnickova L, Glatz Z, Sterbova H. Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic. |
| Capillary electrochromatography (CEC) using polymer-based monolithic stationary phase has been developed as a promising method for the determination of lignans of Schisandra chinensis. The columns were prepared by in situ copolymerisation of acrylamide, N,N'-methylenebisacrylamide, vinylsulfonic acid and lauryl acrylate in presence of poly(ethylene glycol) as a porogenic agent. The columns [33 cm (24.5 cm effective length) x 75 microm I.D.] were successfully used to analyse and quantify the major lignans in extract of the seeds of Schisandra chinensis. Good separations were achieved in less than 35 min. The calibration graphs were linear in the range 0.025-1.0 mg/ml of given lignan with correlation coefficients between 0.9951 and 0.9996. The inter-day reproducibility of the peak area were below 3.9% and the inter-day reproducibility of the migration time were below 4.2%. The results of quantitative CEC analyses were compared with those obtained by reversed-phase HPLC, the levels of schizandrin, gomisin A, gomisin N and wuweizisu C determined by CEC were in a good agreement with those determined by HPLC. |
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26: Drug Metab Dispos. 2001 Apr;29(4 Pt 1):381-8.
Metabolism of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) by human liver microsomes: characterization of metabolic pathways and of cytochrome P450 isoforms involved.
Baek MS, Kim JY, Myung SW. Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul , Korea . |
| Metabolic fate of DDB and identification of P450 isozymes involved in the metabolism of DDB were investigated in human liver microsomes. DDB was rapidly metabolized to five different metabolites, and the structures of each metabolite were characterized based on UV, mass, and NMR spectral analyses. The major metabolic pathways of DDB in human liver microsomes were identified as O-demethylation of the carboxymethyl moiety (M4) and demethylenation of the methylenedioxyphenyl group (M2). The intramolecular lactonization between the hydroxyl group at the C6 and carboxymethyl group at the C2' of M2 resulted in the generation of M5, which was either hydrolyzed to its hydrolyzed derivative (M1) or further metabolized to the O-demethylated derivative (M3). The interconversion of M1, M2, and M5 took place nonenzymatically depending on the solvent condition. M5 was predominantly detected at the acidic condition, whereas M1 was preferentially detected at the basic environment. Cytochrome P450 (P450) isoform(s) involved in the metabolism of DDB was identified using several in vitro approaches. Chemical inhibition using isoform-selective P450 inhibitors, correlation of DDB metabolites formation with several isoform-specific P450 activities in a panel of liver microsomes, metabolism by microsomes derived from P450 cDNA-expressed B-lymphoblastoid cells, and immunoinhibition by isoform-specific anti-P450 antibodies collectively indicated that CYP1A2, CYP2C9, and CYP3A4 are responsible for the metabolism of DDB. O-Dealkylation of the carboxymethyl group was preferentially catalyzed by CYP1A2, whereas demethylenation of the methylenedioxyphenyl moiety was catalyzed by CYP3A4 and CYP2C9. |
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27: J Pharm Biomed Anal. 2001 Mar;24(5-6):1049-54.
Simultaneous determination of quercetin, kaempferol and (E)-cinnamic acid in vegetative organs of Schisandra chinensis Baill. by HPLC.
Sladkovsky R, Solich P, Opletal L. Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Hradec Kralove, Czech Republic. |
| A reversed-phase high-performance liquid chromatographic (RP-HPLC) separation method with UV spectrophotometric detection has been developed for the determination of major components in leaves and caulomas of Schisandra chinensis Baill. The flavonols (quercetin and kaempferol) and (E)-cinnamic acid were analysed after extraction with alcohol from the dry plant material. Identification was based on retention times and UV spectra by comparison with commercial standards. Quercetin, kaempferol and (E)-cinnamic acid were separated within 12 min using acetonitrile-aqueous 0.05% ortho-phosphoric acid (40:60 v/v) mobile phase. The method has been successfully applied for the quantitative analysis of all three major components in several samples from different harvests using propylparaben as the internal standard. |
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28: J Pharm Pharmacol. 2000 Sep;52(9):1099-103.
Pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5 ,6,5',6'dimethylenedioxybiphenyl-2-carboxylic acid-2'-carboxylate monohydrochloride in rats with CCl4-induced acute hepatic failure.
Oh SY, Lee CH, Ku YS. College of Pharmacy , Ewha Womans University , Seodaemun-Gu, Seoul , Korea . |
| The pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybip henyl-2-carboxylic acid-2'-carboxylate monohydrochloride (DDB-S) have been investigated in rats with CCl4-induced acute hepatic failure. To study the pharmacokinetics of DDB-S, rats were divided into a control group and a CCl4-intoxicated group. DDB-S 50 mg kg(-1) was administered by intravenous bolus injection to both groups of rats. In the CCl4-intoxicated rats the plasma concentrations of DDB-S were significantly higher, the area under the plasma concentration-time curve from time zero to time infinity was significantly greater (6-46 vs 3.34 mg min mL(-1)), and the total body (7.74 vs 15.0 mL min(-1) kg(-1)), renal (2.55 vs 5.10 mL min(-1) kg(-1)), nonrenal (5.07 vs 9.65 mL min(-1) kg(-1)), and biliary (1.48 vs 2.69 mL min(-1) kg(-1)) clearances were significantly slower compared with the control rats. This could be due to decreased hepatic cytochrome P450 activity and impaired kidney function induced by CCl4. To study the hepatoprotective effects of DDB-S, rats were divided into three groups, control rats and CCl4-intoxicated rats with or without DDB-S pretreatment (50 mg kg(-1) i.p.). The effects of DDB-S pretreatment on CCl4-induced liver injury were considerable; the serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly lower by 54.3, 44.6 and 67.2%, respectively, compared with the CCl4-intoxicated-only group. In an in-vitro study, rat hepatocytes were exposed to fresh medium containing 10 mM CCl4 and various concentrations of DDB-S (10 or 100 microg mL(-1)). The levels of alanine transaminase and aspartate transaminase in the medium were measured as an indicator of hepatocyte injury. DDB-S dose-dependently decreased the levels of alanine transaminase and aspartate transaminase compared with CCl4-intoxication only. These results indicate that DDB-S has hepatoprotective activity. |
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29: Planta Med. 2000 Aug;66(6):521-5.
Improvement of phase I drug metabolism with Schisandra chinensis against CCl4 hepatotoxicity in a rat model.
Zhu M, Yeung RY, Lin KF. Department of Pharmacy, Chinese University of Hong Kong , Hong Kong . |
| The seed extract of Schisandra chinensis was investigated in the rat for its restorative or therapeutic effect on Phase I hepatic drug metabolism following intoxication by carbon tetrachloride (CCl4). Male Sprague Dawley rats (220-250 g) were divided into two sets, one included rats with or without CCl4 intoxication, the other included CCl4 intoxicated rats with or without treatment of Schisandra extract. With the treatment regimen, rats received four oral doses of Schisandra (160 mg/kg) or the same volume of water at 8, 24, 32 and 48 h after CCl4 intoxication. A single oral dose (80 mg/kg) of antipyrine, a conventional probe for oxidative drug metabolism, was then administered. The levels of liver serum transaminases and cytochrome P450 were measured and the pharmacokinetics of antipyrine were assessed using a non-compartmental approach via WinNonlin. In comparison to the rats without CCl4 intoxication (t1/2: 2.2 +/- 0.9 h; Cl/F: 0.30 +/- 0.01 L/h/Kg; P450: 0.611 +/- 0.190 nmol/mg protein), CCl4 administration significantly decreased elimination (t1/2: 12.0 +/- 3.9 h) and oral clearance (Cl/F: 0.049 +/- 0.018 L/h/kg) of antipyrine, and markedly reduced the content of P450 (0.075 +/- 0.011 nmol/mg protein). Data obtained from intoxicated animals treated by Schisandra extract, compared to those without treatment, showed significant (p < 0.05) improvement in the t1/2 (4.45 +/- 1.7 h) and Cl/F (0.096 +/- 0.018 ml/h) estimates of antipyrine and a 2-3 fold increase in P450 level (0.190 +/- 0.072 nmol/mg protein). Findings in this study suggest that the seed extract of Schisandra appeared to be a promising agent for the improvement of Phase I oxidative metabolism in the liver damaged by CCl4. |
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30: Liver. 2000 Jul;20(4):319-29.
Inhibition of lipopolysaccharide-induced I-kappaB degradation and tumor necrosis factor-alpha expression by dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB): minor role in hepatic detoxifying enzyme expression.
Kim SG, Kim HJ, Choi SH. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University , Korea . |
| AIMS/BACKGROUND: Dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) is active against a variety of hepatotoxins and has been used as a curative agent for patients with acute and chronic viral hepatitis. Effects of DDB on the expression of xenobiotic-metabolizing enzymes and on nuclear factor-kappaB (NF-kappaB) activation and tumor necrosis factor-alpha (TNF-alpha) production by lipopolysaccharide (LPS), an endotoxin involved in inflammatory responses, were examined in rats and in RAW264.7 cells to investigate mechanistic aspects. METHODS: Expression of hepatic cytochrome P450s, microsomal epoxide hydrolase and glutathione S-transferases was determined by immunoblot and Northern blot analyses. Activation of hepatic NF-kappaB and I-kappaBalpha degradation was assessed by gel mobility shift and immunoblot analyses, respectively. LPS-induced TNF-alpha expression was monitored in rats and in RAW264.7 cells by enzyme-linked immunosorbent assay and/or reverse transcription-polymerase chain reaction analysis. RESULTS: DDB failed to alter the expression of hepatic cytochrome P450 1A and 2C11, microsomal epoxide hydrolase and glutathione S-transferases in rats with slight inhibition of P450 2E1 expression, but induced P450 2B1/2. Pretreatment of rats with DDB prevented LPS-induced hepatic I-kappaBalpha degradation and the resultant NF-kappaB activation, and inhibited the LPS-induced plasma TNF-alpha protein and hepatic TNF-alpha mRNA expression in a dose-dependent manner. LPS-induced I-kappaBalpha degradation and TNF-alpha production were also inhibited by DDB in RAW264.7 cells, which was consistent with the results in rats. CONCLUSIONS: The present study demonstrated that DDB may inhibit inflammatory responses in association with reduction of NF-kappaB activation through prevention of I-kappaBalpha degradation and subsequent TNF-alpha production, but not with modulation of the detoxifying enzyme expression. |
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31: Mol Cell Biochem. 2000 May;208(1-2):151-5.
Schisandrin B protects against menadione-induced hepatotoxicity by enhancing DT-diaphorase activity.
Ip SP, Yiu HY, Ko KM.
Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, P.R. China. |
| Pretreating mice with schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, at a daily dose of 1 mmol/kg for 3 days protected against menadione-induced hepatic oxidative damage in mice, as evidenced by decreases in plasma alanine aminotransferase activity (78%) and hepatic malondialdehyde level (70%), when compared with the menadione intoxicated control. In order to define the biochemical mechanism involved in the hepatoprotection afforded by Sch B pretreatment, we examined the activity of DT-diaphorase (DTD) in hepatocytes isolated from Sch B pretreated rats. Hepatocytes isolated from Sch B pretreated (a daily dose of 1 mmol/kg for 3 days) rats showed a significant increase (25%) in DTD activity. The increase in DTD activity was associated with the enhanced rate of menadione elimination in the hepatocyte culture. The ensemble of results suggests that the ability of Sch B pretreatment to enhance hepatocellular DTD activity may at least in part be attributed to the protection against menadione hepatotoxicity. |
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32: Mol Cell Biochem. 2000 Feb;205(1-2):111-4.
Differential effect of schisandrin B and dimethyl diphenyl bicarboxylate (DDB) on hepatic mitochondrial glutathione redox status in carbon tetrachloride intoxicated mice.
Ip SP. Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay , PR China. |
| The effects of schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, and dimethyl diphenyl bicarboxylate (DDB), a synthetic intermediate of schisandrin C (also a dibenzocyclooctadiene derivative), on hepatic mitochondrial glutathione redox status in control and carbon tetrachloride (CCl4)-intoxicated mice were examined. Treating mice with Sch B or DDB at a daily oral dose of 1 mmol/kg for 3 d did not produce any significant alterations in plasma alanine aminotransferase (ALT) and sorbital dehydrogenase (SDH) activities. CCl4 treatment caused drastic increases in both plasma ALT and SDH activities in mice. Pretreating mice with Sch B or DDB at the same dosage regimen significantly suppressed the CCl4-induced increase in plasma ALT activity, with the inhibitory effect of Sch B being much more potent. Sch B, but not DDB, pretreatment could also decrease the plasma SDH activity in CCl4-intoxicated mice. The lowering of plasma SDH activity, indicative of hepatoprotection against CCl4 toxicity, by Sch B pretreatment was associated with an enhancement in hepatic mitochondrial glutathione redox status as well as an increase in mitochondrial glutathione reductase (mtGRD) activity in both non-CCl4 and CCl4-treated mice. DDB pretreatment, though enhancing both hepatic mitochondrial glutathione redox status and mtGRD activity in control animals, did not produce any beneficial effect in CCl4-treated mice. The difference in hepatoprotective action against CCl4 toxicity between Sch B and DDB may therefore be related to their ability to maintain hepatic mitochondrial glutathione redox status under oxidative stress condition. |
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33: J Ethnopharmacol. 1999 Oct;67(1):61-8.
Evaluation of the protective effects of Schisandra chinensis on Phase I drug metabolism using a CCl4 intoxication model.
Zhu M. Department of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. |
| To evaluate the potential activity of Schisandra chinensis in restoring hepatic drug metabolism in CCl4 damaged liver, antipyrine was employed as a probe for the possible effects of the herb on Phase I oxidative metabolism in rats. Schisandra lignan fraction (160 mg/kg) was given orally to male Sprague-Dawley rats (220-240 g) 30 min or 6 h before CCl4 intoxication (4 ml/kg, s.c.). Following a single oral dose of antipyrine (80 mg/kg) to the rats with damaged liver, the pharmacokinetics of antipyrine in whole blood were determined and levels of liver enzymes, e.g. SGPT, SGOT, and cytochrome P450 were measured. Pharmacokinetic parameters for antipyrine were estimated using noncompartmental analysis. Results indicated that CCl4 significantly increased the elimination half-life (t(1/2)) of antipyrine from 2.59 +/- 1.04 to 11.25 +/- 3.91 h (P < 0.001) and decreased its clearance (CL) from 65.94 to 10.84 ml/h as compared to control. Pretreatment with the Schisandra lignan fraction 30 min or 6 h before intoxication significantly (P < 0.001) improved antipyrine elimination by reducing its t(1/2) to 3.30 +/- 0.52 and 3.58 +/- 1.05 h, respectively. The corresponding improvements observed for CL, i.e. 49.06 +/- 21.75 ml/h (P < 0.01); 21.10 +/- 10.42 ml/h (P < 0.05), were also substantial. Moreover, normalization of SGPT, SGOT and P450 levels was observed with the two Schisandra pretreatment schedules. In conclusion, Schisandra lignans exhibited strong protective effect on Phase I oxidative metabolism in the liver damaged by CCl4. Furthermore, pretreatment of Schisandra 30 min before intoxication showed a more pronounced effect than that of the 6 h pretreatment. The current pharmacokinetic approach allowed the protective effects of Schisandra on oxidative drug metabolism in damaged liver to be systemically examined and will certainly help in the evaluation of hepato-protectants obtained from natural sources. |
34: J Chromatogr Sci. 1999 Dec;37(12):457-61.
Effect of plant matrix and fluid ethanol concentration on supercritical fluid extraction efficiency of schisandrin derivatives.
Kim Y. College of Pharmacy, Seoul National University , Korea .
An investigation of the effect of plant matrix on the supercritical fluid extraction efficiency of five schisandrin derivatives is reported, exhibiting a great difference with respect to extraction efficiency depending on the matrix. Pure supercritical CO2 at 60 degrees C and 34.0 MPa cannot fully recover schisandrin derivatives from the leaves as much as from the other matrices. Only 36.9% of these compounds are extracted from leaves of Schisandra chinensis by supercritical CO2 in comparison with organic solvent extraction. However, more than 80% of schisandrin derivatives are obtained from both stem and fruit parts. Ethanol addition also shows a different effect depending on plant matrix; that is, CO2 modified with 10% ethanol could enhance the yield of schisandrin derivatives from leaves by four times when compared with that of pure CO2, but it has little effect on both stems and fruits. |
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35: Mol Cell Biochem. 1999 Jun;196(1-2):151-6.
Schisandrin B protects against myocardial ischemia-reperfusion injury by enhancing myocardial glutathione antioxidant status.
Yim TK, Ko KM.
Department of Biochemistry, The Hong Kong University of Science and Technology, PR China. |
| The effects of Schisandrin B (Sch B) and dimethyl-4,4'-dimethoxy-5,6,5',6'dimethylene-dioxy-biphenyl-2,2'-+ ++bicarboxylate (DDB) treatment on myocardial ischemia-reperfusion (IR) injury in isolated perfused rat hearts were examined under both in vitro and ex vivo conditions. In vitro administration of liposome-entrapped Sch B or DDB during reperfusion did not protect against myocardial IR injury, whereas ascorbic acid or Trolox supplemented perfusate produced protective effect, as evidenced by the significant decrease in the extent of lactate dehydrogenase leakage as well as an improvement in contractile force recovery. Myocardial protection afforded by N-acetyl-L-cysteine supplemented perfusate was not accompanied by the enhancement in contractile force recovery. In ex vivo experiment, pretreatment of Sch B (0.6/1.2 mmol/kg/day x 3) protected against IR-induced myocardial damage in a dose-dependent manner. The myocardial protection was associated with an enhancement in myocardial glutathione antioxidant status, as indicated by significant reductions in both the extent of IR-induced reduced glutathione depletion and inhibition of Se-glutathione peroxidase and glutathione reductase activities. In contrast, the inability of DDB pretreatment to enhance myocardial glutathione antioxidant status resulted in a failure in preventing IR injury. The ensemble of results suggests that the myocardial protection afforded by Sch B pretreatment, which was unlikely due to free radical scavenging action, may be mainly mediated by the enhancement of myocardial glutathione antioxidant status, particularly under oxidative stress conditions. |
36: Zhongguo Yao Li Xue Bao. 1998 Jul;19(4):313-6.
Structure-activity relationship of schisandrins in enhancing liver mitochondrial glutathione status in CCl4-poisoned mice.
Ip SP, Che CT, Ko KM. Department of Biochemistry, Hong Kong University of Science & Technology, Clear Water Bay, China.
AIM: To explore whether the methylenedioxy group and cyclooctadiene ring of the dibenzocyclooctadiene skeleton of schisandrins (Sch) play a role in the liver mitochondrial glutathione status enhancing activity. METHOD: The effects of three dibenzocyclooctadiene derivatives, Sch A, Sch B, Sch C, and a synthetic intermediate of Sch C, (dimethyl biphenyl dicarboxylate, DBD) on carbon tetrachloride (CCl4)-hepatotoxicity and liver mitochondrial glutathione status were examined in mice. RESULTS: Pretreating mice with intragastric Sch B, Sch C, or DBD 1.mmol.kg-1.d-1 for 3 d protected against CCl4-hepatotoxicity. The hepatoprotection afforded by Sch B or Sch C pretreatment was associated with increases in liver mitochondrial reduced glutathione (mtGSH) level and glutathione reductase (mtGRD) activity, an indication of enhanced mitochondrial glutathione status. In contrast, the hepatoprotective action of DBD was not accompanied by any detectable changes in mtGSH level and mtGRD activity. CONCLUSION: Both the methylenedioxy group and the cyclooctadiene ring of the dibenzocyclooctadiene molecule are important structural determinants in the enhancement of liver mitochondrial glutathione status.
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37: Phytother Res. 1999 May;13(3):256-7.
Effects of Fructus schizandrae on cycloheximide-induced amnesia in rats.
Hsieh MT, Tsai ML, Peng WH. Institute of Chinese Pharmaceutical Sciences, China Medical College, Taichung, Taiwan, R.O.C. |
| The effects of Fructus Schisandrae (Schizandra Chinensis, (FS) on cycloheximide (CXM)-induced amnesia by using a passive avoidance task were studied in rats. FS at 0.25 and 0.75 g/kg administered for 1 week significantly prolonged the CXM-shortened step-through latency (STL). Of the fractions (n-hexane, chloroform and water), only the water fraction at 25 mg/kg administered for 1 week prolonged the CXM-shortened STL. These results suggest that the water fraction is the main active fraction of FS. |
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38: Phytomedicine. 1999 Mar;6(1):17-26.
Effects of heavy physical exercise and adaptogens on nitric oxide content in human saliva.
Panossian AG. Guelbenkian Research Laboratory of Armenian Drug and Medical Technology Agency, Yerevan , Armenia .
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Since heavy physical exercise increases the content of nitric oxide and cortisol in blood and saliva, standardized extracts of the adaptogen herbal drugs Schizandra chinensis and Bryonia alba roots were applied to several groups of athletes in a placebo controlled double blind study. In the beginning of a test with athletes Schizandra chinensis and Bryonia alba extracts increased the concentration of NO and cortisol in blood plasma and saliva similar to athletes with heavy physical exercise. These results correlate with an increased physical performance in athletes taking adaptogens versus athletes taking placebo. In contrast after treatment with the adaptogen heavy physical exercise does not increase salivary NO and cortisol in athletes, whereas athletes treated with placebo heavy physical exercise increased salivary NO. These results show that the salivary NO test can be used both for evaluation of physical loading and stress protective effect of an adaptogen.
Publication Types:
• Clinical Trial
• Randomized Controlled Trial |
39: Biol Pharm Bull. 1999 Mar;22(3):265-7.
Structure-activity relationships of lignans from Schisandra chinensis as platelet activating factor antagonists.
Lee IS. Biotechnology Research Division, Korea Research Institute of Bioscience and Biotechnology, Taejon .
We studied the structure-activity relationships of lignans from Schisandra chinensis and their derivatives as platelet activating factor (PAF) antagonists. Strong activity was shown in lignans without an ester group at C-6, a hydroxyl group at C-7 or a methylene dioxy moiety and with an R-biphenyl configuration. 6(7)-Dehydroschisandrol A, a derivative of schisandrol A, showed the highest activity (IC50, 2.1x10(-6) M) in this study.
40: Biol Pharm Bull. 1999 Jan;22(1):93-5.
Effect of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'- dicarboxylate (DDB) on chemical-induced liver injury.
Kim SN, Kim SY, Yim HK, Lee WY , Ham KS , Kim SK, Yoon MY, Kim YC.
College of Pharmacy , Seoul National University , Korea .
The effects of orally administered dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene-dioxybiphenyl-2,2'-d icarboxylate (DDB) on the hepatotoxicity induced by carbon tetrachloride, acetaminophen or ethanol were investigated in rats and mice. Either single or repeated DDB pretreatment (50 or 200 mg/kg) did not alter the hepatotoxicity induced by carbon tetrachloride (0.2 or 1.0 ml/kg, i.p.) in female rats as indicated by increases in the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SDH) in serum. The hepatotoxicity of acetaminophen (350 mg/kg, i.p.) was also unaffected in male mice pretreated with DDB (50 mg/kg/d) for a week. However, DDB administration (50 mg/kg/d for 7 d) decreased the hepatic fatty degeneration induced by repeated ethanol treatment (0.75 g/kg, i.p., x2 times a day for a week) in rats as shown by the accumulation of triglycerides and cholesterol in the liver. Malondialdehyde (MDA) formation in liver homogenates was inhibited by DDB treatment. The significance of the action of DDB on alcoholic fatty liver generation in clinical settings is discussed. |
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41: Biochem Pharmacol. 1999 Jan 1;57(1):77-81.
Methylenedioxy group and cyclooctadiene ring as structural determinants of schisandrin in protecting against myocardial ischemia-reperfusion injury in rats.
Yim TK, Ko KM. Department of Biochemistry, The Hong Kong University of Science & Technology, PR China. |
| As a preliminary investigation to exploring whether the methylenedioxy group and the cyclooctadiene ring of the dibenzo[a,c]cyclooctadiene (schisandrin) molecule plays an important role in the protection against myocardial ischemia-reperfusion (IR) injury, we examined the effects of three schisandrins, namely schisandrin A (Sch A), schisandrin B (Sch B), and schisandrin C (Sch C), and the effect of dimethyl-4,-4'-dimethoxy-5,6,5',6'-dimethylene-dioxy-biphenyl-2,2' -bicarboxylate (DDB), an intermediate compound derived from the synthesis of Sch C, on myocardial IR injury in isolated Langendorff-perfused rat hearts. While pretreating rats with Sch A or DDB at a daily oral dose of 1.2 mmol/kg for 3 days did not protect the isolated-perfused hearts against IR-induced damage, pretreatment with Sch B or Sch C at the same dosage regimen produced cardioprotective action. The extent of cardioprotection afforded by Sch B or Sch C pretreatment correlated well with the degree of enhancement in myocardial glutathione antioxidant status, as indicated by significant increases in the tissue-reduced glutathione level and Se-glutathione peroxidase (EC 1.11.1.9), glutathione transferases (EC 2.5.1.18), and glutathione reductase (EC 1.6.4.2) activities in ischemic-reperfused hearts when compared with the unpretreated IR control. Our results indicate that both the methylenedioxy group and the cyclooctadiene ring of the schisandrin molecule are important structural determinants in mediating the protection against myocardial IR injury. |
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42: Eksp Klin Farmakol. 1998 May-Jun;61(3):61-3.
[The effect of elton, leveton, fitoton and adapton on the work capacity of experimental animals]
Azizov AP. Department of Biologically Active Substances, All-Russian Research Institute of Physical Culture, Mowcow , Russia . |
| The test with running on a treadbane showed a 56% increase of working capacity in the control group of male albino mice on the 20th day of training. Oral administration of elton, leveton, phytoton, and adapton, as well as Leuzea and Rhodiola extracts and Schisandra chinensis tincture caused a statistically significant increase in the time of running on the treadbane of animals by the 10th day of medication. The increase in the working capacity of the animals was more marked by the 20th day. In the test of swimming "to the limit" adapton, phytoton, leveton, and elton increased to a greater extent the working capacity of male albino rats in diminishing succession (from 213 to 168%). Schisandra tincture and Rhodiola and Leuzea extracts also increased the swimming time of the animals by 135-159%. |
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43: Biochem Pharmacol. 1997 Jul 15;54(2):317-9.
Methylenedioxy group as determinant of schisandrin in enhancing hepatic mitochondrial glutathione in carbon tetrachloride-intoxicated mice.
Ip SP. Department of Biochemistry, The Hong Kong University of Science & Technology, Clear Water Bay . |
| As a preliminary approach to exploring whether the methylenedioxy group of the dibenzocyclooctadiene skeleton of schisandrins plays an important role in hepatic mitochondrial-reduced glutathione (GSH) stimulatory activity, we examined the effects of three schisandrins, namely schisandrin A (Sch A), schisandrin B (Sch B), and schisandrin C (Sch C), on carbon tetrachloride (CCl4) hepatotoxicity and hepatic mitochondrial GSH status in mice. Pretreating mice with Sch A at a daily oral dose of 1 mmol/kg for 3 days did not protect against CCl4 hepatotoxicity, whereas pretreatment with Sch B or Sch C at the same dosage regimen produced almost complete protection. The hepatoprotection afforded by Sch B or Sch C pretreatment was associated with significant increases in the hepatic mitochondrial GSH level and glutathione reductase (EC 1.6.4.2) activity. Our results indicate that the methylenedioxy group of the dibenzocyclooctadiene skeleton of schisandrin is an important structural determinant in the stimulation of hepatic mitochondrial GSH, particularly under conditions of CCl4 intoxication. |
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44: Cancer Lett. 1996 Nov 12;108(1):67-72.
Reversing effect of dimethyl-4,4'-dimethoxy-5,6,5', 6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) on the phenotypes of human hepatocarcinoma cells line.
Liu Z. Department of Pharmacology, Chinese Academy of Medical Sciences, Peking Union Medical University, Beijing, PR China. |
| When human Bel-7402 hepatocarcinoma cell line grew in a medium containing 10(-4) M dimethyl-4,4'-dimethoxy-5,6,5', 6'-dimethylenedioxybiphynyl-2,2'-dicarboxylate (DDB), the secretion of alpha-fetoprotein (AFP) was significantly lower than the control cells, whereas the albumin (ALB) secretion was markedly higher. The activity of gamma-glutamultranspepeidase (gamma-GT) in DDB-treated cells markedly decreased in comparison with the control cells. On the contrary, the activity of tyrosine-alpha-ketoglutarate transaminase (TAT) was higher in DDB-treated cells than in control cells. DDB (10(-4) M) could significantly increase the content of cAMP in Bel-7402 cells, and also enhance the expression of anti-oncogene p53. The results suggest that DDB has reversing effects on the phenotypes of the human Bel-7402 hepatocarcinoma cell line. |
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45: Pharmacol Toxicol. 1996 Jun;78(6):413-6.
Effect of a lignan-enriched extract of Schisandra chinensis on aflatoxin B1 and cadmium chloride-induced hepatotoxicity in rats.
Ip SP, Mak DH, Li PC. Department of Biochemistry, Hong Kong University of Science & Technology, Hong Kong. |
| Treatment of rats with a lignan-enriched extract of the fruit of Schisandra chinensis could enhance hepatic antioxidant/detoxification system, as indicated by increases in hepatic reduced glutathione (GSH) level as well as hepatic glutathione reductase and glutathione S-transferase activities. The hepatoprotective action was evident after aflatoxin beta 1 or cadmium chloride (Cd) challenge. Schisandra chinensis pretreatment protected against aflatoxin B1-or Cd-induced hepatocellular damage in rats. However, pretreating rats with alpha-tocopherol acetate (vitamin E) did not protect against hepatic damage induced by both toxins. Results from the present as well as our previous studies demonstrate that the hepatoprotection afforded by Schisandra chinensis pretreatment is not hepatotoxin specific. Schisandra chinensis seems to be more effective than vitamin E in protecting against aflatoxin B1 and Cd toxicity. The mechanism of hepatoprotection afforded by Schisandra chinensis pretreatment may involve facilitation of both antioxidant and detoxification processes in the liver. |
46: Zhonghua Yi Xue Za Zhi. 1996 Mar;76(3):214-7.
[Inducing effect of dimethy-4, 4'-dimethoxy-5, 6,5',6-dimethylenedioxybipheny-2, 2'-dicarboxylate (DDB) on differentiation of leukemia HL-60 cells]
Liu Z. Department of Pharmacology, Chinese Academy of Medical Sciences, Peking Union Medical College , Beijing .
OBJECTIVE: To study the effects of anti-hepatitis drug, DDB, on leukemia cell line HL-60. METHOD: Cytobiological methods were used. RESULT: DDB was inhibited the proliferation of HL-60 cells. About 50% of HL-60 cells treated with DDB (10(-4)mol/L) for 6 days exhibited NBT reduction, and phagocytosis activity was also enhanced by DDB (10(-4)mol/L) for 4 days. The HL-60 cells treated with DDB turned out to be mature granulocytes morphologically. CONCLUSION: The activity of acid phosphatase in DDB-treated HL-60 cells was significantly increased. DDB can induce HL-60 cells to differentiate along granulocyte lineage. |
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47: Am J Chin Med. 1996;24(3-4):255-62.
Schisandra chinensis-dependent myocardial protective action of sheng-mai-san in rats.
Li PC. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. |
| Sheng-Mai-San (SMS), a traditional Chinese formulation used for the treatment of coronary heart disease, is comprised of Radix Ginseng, Fructus Schisandrae and Radix Ophiopogonis. Pretreatment with a lignan-enriched SMS (17 g/kg/day x 3, p.o.) was found effective in protection against isoproterenol-induced myocardial injury in rats, and in ischemia-reperfusion injury in isolated perfused hearts prepared from pretreated animals. Results obtained from pretreatment studies using extracts prepared by mixing various combinations of the three component herbs indicate that the major myocardial protective component in SMS is the lignan-enriched extract of Fructus Schisandrae. |
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48: Free Radic Biol Med. 1996;21(5):709-12.
Schisandrin B protects against carbon tetrachloride toxicity by enhancing the mitochondrial glutathione redox status in mouse liver.
Ip SP, Poon MK, Che CT. Department of Biochemistry, Hong Kong University of Science & Technology, Hong Kong. |
| Previous studies in our laboratory have demonstrated the effect of Schisandrin B (Sch B),an active ingredient of the fruit of Schisandra chinensis, on enhancing the hepatic glutathione antioxidant system in mice, as evidenced by the hepatoprotection against carbon tetrachloride (CCl4) toxicity. In the present study, the mechanism involved in the hepatoprotection afforded by Sch B treatment was investigated. Treating female Balb/c mice with 1, 3-bis(2-chloroethyl)-1-nitrosourea, an inhibitor of glutathione reductase (GRD), at a dose of 2 mmol/kg (i.p.) did not abrogate the hepatoprotective action of Sch B in CCl4-treated mice. The result indicates that the increased activity of hepatic GRD is not ascribable to the hepatoprotective action of Sch B. In control mice, the same Sch B treatment regimen caused an enhancement in hepatic mitochondrial glutathione redox status, as indicated by the significant increase and decrease in reduced and oxidized glutathione levels, respectively. While the CCl4 intoxication greatly impaired mitochondrial glutathione redox status, the beneficial effect of Sch B treatment became more evident after CCl4 challenge. Our results strongly suggest that the mechanism of hepatoprotection afforded by Sch B treatment may involve the enhancement of mitochondrial glutathione redox status. |
49: Yao Xue Xue Bao. 1996;31(2):101-6.
[Effect of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2, 2'-dicarboxylate (DDB) on several phenotypes of Bel-7402 hepatocarcinoma cell line and its mechanism]
Liu ZY, Cui Q, Liu GT.
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing.
DDB is a hepatoprotectant and has been widely used for the treatment of chronic viral hepatitis in China . The drug markedly improved the abnormal liver function particularly in lowering the elevated serum transaminases in patients. It is known that there is a close correlation between primary hepatocarcinoma and chronic viral hepatitis. The aim of the present study is to evaluate the effect of DDB on hepatocarcinoma cell line. The results showed that the growth and clonogenicity of Bel-7402 human hepatocarcinoma cell line cultured with DDB were markedly inhibited. The nucleoles of the cells treated with DDB disappeared or their numbers and nucleus/cytoplasm ratio decreased under electron microscopic observation. DDB at the concentration of 10(-4) mol.L-1 significantly increased the contents of cAMP and calmodulin ( CaM ) in Bel-7402 hepatocarcinoma cells. DDB was also found to inhibit topoisomerase II activity of Bel-7402 hepatocarcinoma cells. These results suggest that the mechanism of inhibition of DDB on several phenotypes of Bel-7402 cell line may be related to its effect on cAMP and CaM content as well as topoisomerase II activity.
50: Zhonghua Yi Xue Za Zhi. 1995 Nov;75(11):676-8, 710.
[Reversing effect of dimethyl-4,4'-dimethoxy-5,6,5'6'-dimethylenedioxybiphenyl-2,2'- dicarboxylate(DDB) on the phenotypes of human hepatocarcinoma cell line]
Liu Z, Liu G, Zhang S.
Department II of Pharmacology, Chinese Academy of Medical Sciences, Beijing .
When human Bel-7402 hepatocarcinoma cell line grew in a medium containing 10(-4)M DDB, the secretion of alpha-fetoprotein (AFP) and the activity of gamma-glutamyl-transpeptidase (gamma-GT) were significantly lower than the control cells, whereas the albumin (ALB) secretion and the activity of tyrosine-alpha-ketoglutarate transaminase (TAT) were markedly increased. DDB at the concentration of 10(-4)M could significantly increase the content of cAMP in Bel-7402 cells, and also suppressed the expressions of oncogene c-myc and hepatocarcinoma marker AFP gene and enhanced the anti-oncogene p53 expression. The results of this paper suggest that DDB has some reversing effects on the phenotypes of human Bel-7402 hepatocarcinoma cell line. |
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51: Planta Med. 1995 Apr;61(2):134-7.
Effect of a lignan-enriched fructus schisandrae extract on hepatic glutathione status in rats: protection against carbon tetrachloride toxicity.
Ko KM, Ip SP, Poon MK. Department of Biochemistry, Hong Kong University of Science & Technology, Clear Water Bay, Kowloon. |
| The effect of a lignan-enriched extract of the fruits of Schisandra chinensis (FS) on hepatic glutathione (GSH) status was examined in both control and carbon tetrachloride (CCl4)-treated rats. FS treatment caused a dose-dependent enhancement in hepatic GSH status, as evidenced by significant increases in hepatic GSH level and activities of hepatic glucose-6-phosphate and glutathione reductase (GRD), as well as a decreased susceptibility of hepatic tissue homogenates to in vitro peroxide-induced GSH depletion. The beneficial effect of FS treatment on hepatic GSH status became more evident after CCl4 challenge. Pretreating rats with FS extract at increasing daily doses ranged from 0.2 to 3.2 g/kg for 3 days caused a dose-dependent protection against the CCl4-induced impairment in hepatic GSH status. The enhancement in hepatic GSH status was associated with corresponding decreases in tissue malondialdehyde levels and plasma alanine aminotransferases activities, indicating a significant reduction in the extent of oxidative hepatocellular damage. Our results indicate that the molecular mechanism of hepatoprotection afforded by FS pretreatment may involve the facilitation of GSH regeneration via the GRD-catalyzed and NADPH-mediated reaction. |
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52: Cancer Lett. 1995 Mar 2;89(2):201-5.
Mechanistic study of the inhibition of aflatoxin b1-induced hepatotoxicity by dimethyl 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy biphenyl-2, 2'-dicarboxylate.
Liu TY, Hwua YS, Chao TW. Department of Medical Research, Veterans General Hospital , Taipei , Taiwan , ROC. |
| The mechanism of DDB (dimethyl 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy biphenyl-2,2'-dicarboxylate) prevention of aflatoxin B1 (AFB1)-induced hepatotoxicity in rats has been investigated. Pretreatment of DDB (200 mg/kg) daily for 4 days significantly suppressed (P < 0.05) the AFB1-induced hepatic damage as evidenced by the increase of serum marker enzymes. DDB induced rat hepatic cytochrome P450IA1, IIB1 and glutathione S-transferase activities. The hepatic microsomes derived from DDB treated rats increased the mutation frequency of AFB1 and enhanced the binding of AFB1 to DNA. However, the hepatic S9 fraction from DDB treated rats showed a protective effect against AFB1-induced damage. It is concluded that the protective effect of DDB against AFB1-induced damage might be mediated by the induced glutathione S-transferase activity and not from the accelerated hepatic cytochrome P450 detoxification pathway of AFB1 which was previously believed. |
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53: Toxicol Lett. 1995 Feb;76(1):33-8.
Occurrence of autoimmune antibodies to liver microsomal proteins associated with lethal hepatitis in LEC rats: effects of TJN-101 ((+)-(6S,7S,R-biar)- 5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy-6,7-dimethyl-10,11- methylenedioxy-6-dibenzo[a,c]cyclooctenol) on the development of hepatitis and the autoantibodies.
Yokoi T, Nagayama S, Kajiwara R. Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University , Japan . |
| Long Evans Cinnamon (LEC) rats, that spontaneously develop hepatitis, were found to possess autoantibodies to liver microsomal proteins (anti-LM) before the development of hepatitis. Anti-LM antibody was assumed to appear in association with the lethal hepatitis in the LEC rats. Thus, the purpose of this study was to investigate the effects of an anti-hepatitis drug on the development of hepatitis and the occurrence of the antibody in LEC rats. Mortality, blood biochemical parameters and the titer of serum anti-LM antibody were measured. In control LEC rats, 4 of 8 rats died before 20 weeks of age. In rats treated with TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11 - methylenedioxy-6-dibenzo[a,c]cyclooctenol), 4 of 7 rats died of hepatitis, but the time of death was delayed by 7-10 weeks compared to the control rats. The titer of the anti-LM antibody increased 3-7 weeks before death in the non-survivors in control and TJN-101-treated rats, supporting the idea that anti-LM antibody occurs in association with acute lethal hepatitis. |
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54: Br J Pharmacol. 1994 Nov;113(3):945-53.
Inhibition by gomisin C (a lignan from Schizandra chinensis) of the respiratory burst of rat neutrophils.
Wang JP, Raung SL, Hsu MF. Department of Medical Research, Taichung Veterans General Hospital , Taiwan . |
| 1. The possible mechanisms of action of the inhibitory effect of gomisin C on the respiratory burst of rat neutrophils in vitro was investigated. 2. The peptide formyl-Met-Leu-Phe (FMLP) induced superoxide anion (O2-) formation and O2 consumption, which was inhibited by gomisin C in a concentration-dependent manner (IC50 21.5 +/- 4.2 micrograms ml-1 for O2- formation). Gomisin C also suppressed O2- formation and consumption at low concentrations of phorbol myristate acetate (PMA) with an IC50 value of 26.9 +/- 2.1 micrograms ml-1 for O2- formation. However, gomisin C did not affect the responses induced by a high concentration of PMA. 3. Gomisin C had no effect on O2- generation and uric acid formation in the xanthine-xanthine oxidase system, and failed to alter O2- generation during dihydroxyfumaric acid (DHF) autoxidation, indicating that it does not scavenge superoxide. 4. Like trifluoperazine (TFP), gomisin C attenuated the activity of PMA-activated neutrophil particulate NADPH oxidase in a concentration-dependent manner. 5. Gomisin C reduced the elevations of cytosolic free Ca2+ in neutrophils stimulated by FMLP in the presence or absence of EDTA. Cyclopiazonic acid (CPA) induced the release of Ca2+ from intracellular stores and this was also reduced by gomisin C. However, the Ca2+ influx pathway activated by CPA was not affected by gomisin C. 6. The cellular cyclic AMP level was markedly increased by forskolin, but not by gomisin C. Moreover, the inositol phosphate levels in FMLP-activated neutrophils were not affected by gomisin C. 7. These results show that the inhibitory action of gomisin C on the respiratory burst is not mediated by changes in cellular cyclic AMP or in inositol phosphates, or by scavenging O2- released from neutrophils, but may be mediated partly by the suppression of NADPH oxidase and partly by the decrease of cytosolic Ca2+ released from an agonist-sensitive intracellular store. |
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55: J Ethnopharmacol. 1994 May;42(3):183-91.
The effect of Chinese hepatoprotective medicines on experimental liver injury in mice.
Liu J, Liu Y, Klaassen CD. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City 66160-7417. |
| The purpose of this study was to compare the hepatoprotective effects of seven Chinese herbal compounds/mixtures on four known hepatotoxicants in mice. These compounds include fulvotomentosides oleanolic acid, total saponins of Panax japonicus (Jgs), total saponins of Panax notoginseng (Ngs), sweroside, oxymatrine, and dimethyl dicarboxylate biphenyl (DDB). All have previously been reported to exhibit hepatoprotective effects. Acute liver injury was produced in male CF-1 mice by CCl4, acetaminophen, cadmium chloride and allyl alcohol. Liver damage was assessed by quantifying serum activities of sorbitol dehydrogenase and alanine aminotransferase, as well as by histopathological examination. Fulvomentosides markedly decreased the toxicity produced by all four hepatotoxicants; oleanic acid also remarkably decreased acetaminophen, CCl4 and Cd-induced hepatotoxicity, but had no effect on allyl alcohol; total saponins of Panax japonicus and Panax notoginseng had moderate hepatoprotective effects on these models except that total saponins of Panax japonicus markedly decreased allyl alcohol toxicity; sweroside decreased Cd and CCl4 toxicity but had no effect on the other two hepatotoxicants; oxymatrine only decreased allyl alcohol toxicity; whereas DDB did not protect against any of the hepatotoxicants. The mechanism(s) by which these compounds/mixtures protect against different types of hepatotoxicants requires further investigation. In conclusion, of the seven compounds examined, fulvotomentoside and oleanolic acid appear to be the most effective in protecting against chemical-induced liver injury. |
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56: J Appl Toxicol. 1993 Nov-Dec;13(6):385-8.
Inhibitory effect of gomisi on reductive metabolism of halothane.
Jiaxiang N, Fujii K, Sato N. Department of Anesthesiology and Intensive Care Medicine, School of Medicine, Hiroshima University, Japan. |
| The effect of Gomisi (dried ripe fruit of schizandra chinensis) on chlorodifluoroethylene (CDE) and chlorotrifluoroethane (CTE) formation was investigated. The incubation mixtures for the measurement of reductive metabolites of halothane consisted of liver microsomal suspensions, 3 mM NADPH, extract solution of Gomisi and halothane in 0.1 M potassium phosphate buffer (pH 7.4). The production of CDE and CTE was inhibited by Gomisi in a dose-dependent way. The production were reduced to half in the presence of 0.5% Gomisi extract in the reaction mixture. The results suggest that Gomisi can inhibit the reductive metabolism of halothane in vitro; thus it may protect against halothane-induced hepatitis. |
57: Eur J Drug Metab Pharmacokinet. 1993 Apr-Jun;18(2):155-60.
Aspects of schizandrin metabolism in vitro and in vivo.
Cui YY, Wang MZ.
Institute of Materia Medica , Chinese Academy of Medical Sciences, Beijing .
The metabolic transformation of schizandrin, isolated from the kernel of Schizandra chinensis Bill, was studied in vitro with a phenobarbital induced rat liver microsomal fraction containing the NADPH generating system. The major metabolites were isolated by preparative HPLC and identified as 7,8-dihydroxy-schizandrin, 7,8-dihydroxy-2-demethyl-schizandrin, and 7,8-dihydroxy-3-demethyl-schizandrin by UV, NMR and MS spectral analysis. The 7,8-dihydroxy-schizandrin was confirmed further by comparison with spectral and chromatographic behavior of the authentic compound. The metabolic biotransformation of schizandrin in vivo was also determined. |
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58: Planta Med. 1992 Dec;58(6):489-92.
Effect of Gomisin A (TJN-101) on liver regeneration.
Kubo S, Ohkura Y, Mizoguchi Y. Second Department of Surgery, Osaka City University Medical School , Japan . |
| We studied the effect of TJN-101, a lignan component of Schisandra fruits (Schisandrae fructus), on liver regeneration after partial hepatectomy. TJN-101 was given orally to male Wistar rats 30 min before partial hepatectomy. The mitotic index and the level of DNA synthesis increased after partial hepatectomy and their increase was significantly enhanced by TJN-101. Ornithine decarboxylase (ODC) activity increased in the early stages of liver regeneration and it was also significantly enhanced by TJN-101. Besides, TJN-101 enhanced the increase in hepatic putrescine. These results suggest that TJN-101 stimulates liver regeneration after partial hepatectomy by enhancing ODC activity, which is an important biochemical event in the early stages of liver regeneration. |
59: Zhongguo Yao Li Xue Bao. 1992 Nov;13(6):485-90.
Induction of liver microsomal cytochrome P-450 2B1 by dimethyl diphenyl bicarboxylate in rats.
Li Y. Department of Chemical Biology and Pharmacognosy, College of Pharmacy , Rutgers University , Piscataway , NJ 08855-0789 .
Dimethyl diphenyl bicarboxylate (dimethyl-4,4'-dimethyloxy-5,6,5',6'-dimethylene-dioxy-di phe nyl-2,2'- bicarboxylate, DDB), a synthetic mimic of the natural product schizandrin C, is used in China as a hepatoprotective agent to improve the liver functions of patients with hepatitis or under cancer chemotherapy. In this study, we investigated the effects of DDB on liver microsomal drug-metabolizing enzymes. When male Sprague-Dawley rats were treated with a daily intragastric dose of DDB (200 mg.kg-1) for 3 d, the microsomal pentoxyresorufin dealkylase activity and P-450 2B1 protein levels were markedly increased. The fold increase was lower than that by phenobarbital (75 mg.kg-1, ip once daily x 3 d). The level of P-450 2B1 mRNA was elevated by DDB but the magnitude of the elevation was much less than that caused by phenobarbital. DDB also increased the rates of testosterone hydroxylation at positions 16 beta, 16 alpha, 6 beta, and 2 beta as well as the rate of ethoxyresorufin dealkylation, suggesting moderate increases in the levels of P-450 3A and P-450 1A1 in addition to the huge increase in P-450 2B1. The level of glutathione S-transferase was also slightly increased, but the levels of P-450 2E1 and NAD(P)H: quinone oxidoreductase were not changed. The results indicate that DDB is an inducer of P-450 2B1.
60: Biomed Environ Sci. 1992 Sep;5(3):201-7.
Protective effect of dimethyl-4,4'-dimethoxy-5,6,5', 6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) against carcinogen-induced rat liver nuclear DNA damage.
Qing W, Liu G. Department of Pharmacology, Chinese Academy of Medical Sciences, Beijing .
The protective effect of DDB against carcinogen-induced DNA damage was examined in the present investigation. Preincubation of rat liver nuclei with DDB (1 mmol.L-1) resulted in 60% inhibition of binding of 3H-benzo(a)pyrene to nuclear DNA. Unscheduled DNA synthesis (UDS) induced by aflatoxin B1 (10(-7) mol.L-1) in freshly isolated rat hepatocytes was also inhibited by DDB (10(-6)-10(-3) mol.L-1). Oral administration of DDB at 200 mg.kg-1 once daily for 3 d induced a significant increase of liver cytosol glutathione-S-transferase and microsomal UDPG-transferase activity in mice. These results indicate that DDB is able to directly or indirectly antagonize certain carcinogen-induced DNA damages.
61: Biomed Environ Sci. 1992 Sep;5(3):185-94.
Protective effects of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate on damages of isolated rat hepatocytes induced by carbon tetrachloride and D-galactosamine.
Fu T, Liu G. Department of Pharmacology, Chinese Academy of Medical Sciences, Beijing .
The protective effect of biphenyl dimethyl dicarboxylate (DDB) on chemically induced damages was studied in isolated suspended rat hepatocytes. The experimental results showed that DDB (200 micrograms/10(6) cells) efficiently protected the hepatocytes against carbon tetrachloride (CCl4 10 mmol.L-1) and D-galactosamine (1 mmol.L-1) induced damages. Membranal lipid peroxidation (malondialdehyde, MDA formation) and glutamic pyruvic transaminase (GPT) release from the hepatocytes were markedly decreased. The damage of the cell surfaces of the hepatocytes were also reduced as seen under a scanning electron microscope (SEM). Pretreatment with DDB (300 mg.kg-1) orally ameliorated the reduction of liver glycogen and blood glucose caused by ip injection of D-galactosamine (800 mg.kg-1) in mice. When normal rats were given DDB 300 mg.kg-1 once daily for 10 d, the free ribosomal protein and RNA in the liver increased significantly. These results indicate that DDB is of beneficial effects on both damaged and normal hepatocytes. |
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62: Planta Med. 1992 Aug;58(4):311-3.
Anti-oxidant activity of dibenzocyclooctene lignans isolated from Schisandraceae.
Lu H. Department of Pharmacology, Chinese Academy of Medical Sciences, Beijing . |
| The anti-oxidant activity of nine dibenzocyclooctene lignans isolated from Schisandra chinensis, S. rubriflora, and Kadsura longipedunculata, respectively, was studied. Seven of the 9 lignans (1 mM) inhibited iron/cysteine-induced lipid peroxidation (malondialdehyde, MDA, formation) of rat liver microsomes as well as superoxide anion production in the xanthine/xanthine oxidase system. The actions of the 7 lignans were much more potent than vitamin E at the same concentration of 1 mM. Among the lignans, schisanhenol was the most active one. This compound also prevented the decrease of membrane fluidity of liver microsomes induced by iron/cysteine. The results indicated that seven of the lignans such as schisanhenol have anti-oxidant activities. |
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63: Oncology. 1992;49(1):68-71.
Gomisin A inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin.
Yasukawa K, Ikeya Y, Mitsuhashi H, Iwasaki M, Aburada M, Nakagawa S, Takeuchi M.
College of Pharmacy, Nihon University, Chiba, Japan.
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| Gomisin A, isolated from the fruits of Schisandra chinensis, is one of the dibenzocyclooctadiene lignans. Application of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1 microgram/ear), a tumor-promoting agent, to the ears of mice induces inflammation. Among seven dibenzocyclooctadiene lignans assayed, gomisin A, gomisin J, and wuweizisu C inhibited the inflammatory activity induced by TPA in mice. The ED50 of these compounds for TPA-induced inflammation was 1.4-4.4 mumol. Gomisin A, with an ED50 of 1.4 mumol, showed the strongest inhibitory effect. Furthermore, at 5 mumol/mouse, it markedly suppressed the promotion effect of TPA (2.5 micrograms/mouse) on skin tumor formation in mice following initiation with 7,12-dimethylbenz[a]anthracene (50 micrograms/mouse). It is assumed that the inhibition of tumor promotion by gomisin A is due to its anti-inflammatory activity. |
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64: Free Radic Biol Med. 1992;12(2):127-35.
Antioxidant activity of two dibenzocyclooctene lignans on the aged and ischemic brain in rats.
Xue JY. Department of Pharmacology, Chinese Academy of Medical Sciences, Beijing . |
| The effects of two dibenzocyclooctene lignans on peroxidative damage of aging and ischemic rat brain were studied. Incubation of eight-month-old rat brain mitochondria and membrane suspension with Fe(2+)-cysteine resulted in the formation of malondialdehyde (MDA) and decrease of ATPase activity. Schisanhenol (Sal) (10(-4) M) completely inhibited the peroxidative damages of brain mitochondria and membrane of rats. The swelling and disintegration of brain mitochondria, as well as the reduction of brain membrane fluidity induced by Fe(2+)-cysteine were also prevented by Sal. The results of imitative experiment of ischemia and reperfusion of brain mitochondria and membrane in vitro indicated that Sal significantly impeded production of MDA and loss of ATPase activity induced by reoxygenation following anoxia. Oral administration of Sal induced increase of cytosol glutathione-peroxidase of brain in mice under the condition of reoxygenation following anoxia. The other compound schizandrin (Sin B) also has similar activity. But its potency is weaker than that of Sal. All these results indicate that Sal and Sin B have protective action against oxidative stress. |
65: Yao Xue Xue Bao. 1992;27(1):57-63.
[Metabolic transformation of schizandrin]
Cui YY. Institute of Materia Medica , Chinese Academy of Medical Sciences, Beijing .
The metabolic transformation of schizandrin, isolated from the kernel of Schizandra chinensis Bill, was studied in vitro with phenobarbital-induced rat liver microsomal fractio containing the NADPH-generating system. The major metabolites were isolated by preparative HPLC and identified as 7,8-dihydroxy-schizandrin, 7,8-dihydroxy-2-demethyl schizandrin and 7,8-dihydroxy-3-demethyl schizandrin by UV, NMR, MS spectral analysis. The 7,8-dihydroxy-schizandrin was confirmed further by comparison with spectral and chromatographic behavior of the authentic compound. The metabolic biotransformation of schizandrin in vivo was also determined.
66: Zhonghua Yi Xue Za Zhi. 1991 Dec;71(12):694-6, 48.
[Protective action of biphenyl dimethyl dicarboxylate (DDB) against liver nuclear DNA damage induced by carcinogens]
Qing W, Liu G.
The protective effect of DDB against carcinogen-induced DNA damage was examined in the present investigation. Preincubation of rat liver nuclei with DDB (1 mmol/L) resulted in inhibition of binding of 3H-benzo (a) pyrene to nuclear DNA. The inhibition rate was about 60%. Unscheduled DNA synthesis (UDS) of freshly isolated rat hepatocytes induced by aflatoxin B1 (10(-7) mol/L) was also dose dependently inhibited by DDB (10(-6)-10(-3) mol/L). Oral administration of DDB at 200 mg/kg once daily for 3 days was effective to induce increase of liver cytosol glutathione-S-transferase and microsomal UDPG-transferase in mice. The results indicate that DDB is able directly or indirectly to antagonize certain carcinogen-induced DNA damages.
67: Yakugaku Zasshi. 1991 Oct;111(10):617-20.
[Determination of gomisin A (TJN-101) and its metabolite in rat serum by gas chromatography-mass spectrometry]
Matsuzaki Y, Ishibashi E, Koguchi S, Wakui Y, Takeda S, Aburada M, Oyama T.
Research Institute for Pharmacology, Tsumura & Co., Ibaraki, Japan.
Gomisin A (TJN-101) is one of the lignan components isolated from Schisandra Fruits. A high sensitive and precise method for the determination of TJN-101 and its major metabolite (Met. B) in the rat serum was developed by selected ion monitoring (SIM) with gas chromatography-mass spectrometry (GC/MS) using a fused silica capillary column (SPB-1, Supelco). A 100 microliter serum sample was used for the solid phase extraction. The calibration curves of TJN-101 and Met.B both showed a good linearity between 2.0 and 2000.0 ng/ml. The analytical precision (intra-assay, C.V. less than 4.7%), recoveries (98.4 +/- 10.1%), and detection limit (2 ng/ml) of TJN-101 indicated that this system was suited for the determination of TJN-101 in biological fluid. In case of Met.B, the same results as TJN-101, were obtained. After oral administration of TJN-101 at a dose of 10 mg/kg to male rats, the average values of the maximal serum concentration of TJN-101 and Met.B were 1446.1 +/- 131.8 and 317.4 +/- 18.5 ng/ml, respectively. The serum concentrations of these substances could be monitored sufficiently for 8 h after dosing.
68: Yakugaku Zasshi. 1991 Sep;111(9):531-7.
[Studies on the metabolic fate of gomisin A (TJN-101). II. Absorption and excretion in CCl4 treated rats]
Matsuzaki Y, Matsuzaki T, Ono H. Research Institute for Pharmacology, Tsumura & CO., Ibaraki , Japan .
The absorption and excretion of gomisin A (TJN-101) in rats whose livers were injured by carbon tetrachloride (CCl4) were investigated. After intravenous administration of TJN-101 at a dose of 5 mg/kg, the terminal elimination half-life was 1.5 h in the CCl4-treated rats, which was two times that in normal rats. The mean area under the blood concentration-time curve (AUC) value of TJN-101 in the CCl4-treated rats was twice that in normal rats, and this difference was significant (p less than 0.05). Therefore, the total body clearance of TJN-101 in the CCl4-treated rats decreased less than half of that in normal rats. Similar results were observed when it was administered orally. In the CCl4-treated rats, the serum concentration of Met. B, which was identified as a demethylenated substance and one of major metabolites, tended to decrease more than that in normal rats. On the other hand, the cumulative biliary excretion ratio of TJN-101 in 24 h after dosing in the CCl4-treated rats was 2.5 times that in normal rats. The excretion rate of Met. B in the bile in the CCl4-treated rats tended to be delayed. However, the quantitative variance of biliary excretion of Met. B was not found in both groups. The urinary excretion of TJN-101 or Met. B in 72 h after dosing in the CCl4-treated rats was lower than that in normal rats. Similar results were also observed in excretion in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)
69: Yakugaku Zasshi. 1991 Sep;111(9):524-30.
[Studies on the metabolic fate of gomisin A (TJN-101). I. Absorption in rats]
Matsuzaki Y, Matsuzaki T, Takeda S. Research Institute for Pharmacology, Tsumura & Co., Ibaraki , Japan .
Gomisin A (TJN-101) is one of the lignan components isolated from Schisandra Fruits and expected to have some efficacies in clinical treatment of hepatitis. The serum concentrations of TJN-101 and Met. B, which was identified as a demethylenated substance and one of the major metabolites of TJN-101 in rats, were investigated. After intravenous administration at doses of 1.6, 4.0 and 10 mg/kg of body weight, the serum concentration of TJN-101 decreased biphasically, and the terminal elimination half-life at each dose was about 70 min. Dose-dependency was observed for the area under the concentration-time curve (AUC). On the other hand, the serum concentration of TJN-101 increased rapidly and reached maximum within 15 to 30 min when administered orally. This result was supported by the in situ roop method. The Cmax and the AUC values were not exactly dose-dependent, but the values increased with a dose-up of TJN-101. The biotransformation of TJN-101 to Met. B, was very rapid in both intravenous and oral administrations. The AUC value of Met. B after oral administration of TJN-101 at a dose of 1.6 mg/kg was relatively larger than any other dosages. It suggested that TJN-101 was extensively underwent the first pass effect in rats. More than 80% of TJN-101 was bound with rat serum protein in vitro and in vivo. Therefore, it seems to be necessary to pay attention when it was administered concurrently with high protein binding drugs. |
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70: Planta Med. 1991 Aug;57(4):320-4.
Effect of gomisin A in the prevention of acute hepatic failure induction.
Mizoguchi Y, Kawada N, Ichikawa Y. Third Department of Internal Medicine, Osaka City University Medical School , Japan . |
| Nearly all rats develop massive hepatic cell necrosis and die upon intravenous administration of heat-killed Propionibacterium acnes followed by a small amount of Gram-negative lipopolysaccharide 7 days later. However, when such an experimental liver disorder is induced in rats raised for 4 or more weeks on food containing 0.06% of gomisin A extracted and purified from Schizandra chinensis, the survival rate rises, histological changes of the liver improve remarkably, and splenocyte reactivity to phytohemagglutinin and pokeweed mitogen as well as splenocyte interleukin 1 productivity are retained. These results suggested the possibility that the development of acute hepatic failure may be prevented with the oral administration of gomisin A. |
71: Yao Xue Xue Bao. 1991;26(1):20-4.
[Total synthesis of an analogue of schizandrin]
Chen LH, Xie L, Xie JX. Institute of Materia Medica , Chinese Academy of Medical Sciences, Beijing .
A schizandrin analogue 9, 1, 2, 3, 10, 11, 12-hexamethoxy-6,7-dihydroxy-cis-6,7-dimethyl dibenzocyclooctadiene, is one of the metabolites of schizandrin with comparable anti-convulsion activity. In this paper, compound 9 was synthesized from gallic acid through the following sequence of reactions: methylation, Henry condensation, reduction with Fe-FeCl3-HCl, intermolecular reductive coupling and intramolecular nonphenolic oxidative coupling, totally in seven steps. The intermediate 1,4-diaryl-2,3-dimethyl-2,3-butanediol (7) which is a mixture of erythro and threo isomers was converted by DDQ in TFA into compound 9 and another new compound 10 via a different reaction path.
72: Mem Inst Oswaldo Cruz. 1991;86 Suppl 2:31-7.
Bioactivity of neolignans from fructus Schizandrae.
Li XY. Shanghai Institute of Materia Medica , Chinese Academy of Sciences.
Fructus Schizandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. During past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glycogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schizandrae have an inducing effect on hepatic microsomal drug-metabolizing enzyme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in China as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From natural Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.
Publication Types:
• Review
• Review, Tutorial
73: Zhonghua Yi Xue Za Zhi. 1990 Apr;70(4):201-4, 16.
[Protective effects of biphenyl dimethyl dicarboxylate on damage in isolated rat hepatocytes induced by carbon tetrachloride and D-galactosamine]
Fu T, Liu G.
The protective effect of DDB on chemically induced damages was studied in primary culture of rat hepatocytes. The experimental results showed that DDB (200 ug/10(6) cells) efficiently protected the hepatocytes against carbon tetrachloride (10 mM) and D-galactosamine (1 mM) induced damages. Membrane lipid peroxidation (malondialdehyde, MDA) formation and Glutamic Pyruvic Transaminase (GPT) released from the hepatocytes were markedly decreased. The damage of the cell surfaces of the hepatocytes were also reduced as seen under a scanning electron microscope (SEM). Pretreatment with DDB (300 mg/kg) orally could ameliorate the reduction of liver glycogen and blood glucose caused by injection of D-gal (800 mg/kg i. p) in mice. When normal rats received 300 mg/kg of DDB once daily for 10 days, free ribosomal protein and RNA in the liver increased significantly. These results indicated that DDB is of beneficial effects on damaged and normal hepatocytes.
74: Jpn J Pharmacol. 1990 Feb;52(2):331-6.
Effect of gomisin A (TJN-101) on the arachidonic acid cascade in macrophages.
Ohkura Y, Mizoguchi Y, Morisawa S. Third Department of Internal Medicine, Osaka City University Medical School , Japan .
It has been reported that leukotrienes (LTs) may play a role in inflammatory liver diseases, and several inhibitors of LTs show an inhibitory effect on experimental liver injuries. In this study, the effect of Gomisin A (TJN-101), which is a lignan component of schisandra fruits, on the arachidonic acid cascade in macrophages was examined to explain the mechanisms of the inhibitory effect of TJN-101 on liver injuries. The production of leukotriene B4 was suppressed by treatment with TJN-101, while the activity of 5-lipoxygenase was not affected. The release of arachidonic acid from macrophages stimulated with fMet-Leu-Phe or the Ca++ ionophore A23187 was suppressed by treatment with TJN-101. The activity of phospholipase A2 was not affected by treatment with TJN-101. These results suggested that TJN-101 produces an inhibitory effect on the biosynthesis of LTs by preventing the release of arachidonic acid, and it was thought that the preventive effect on the arachidonic acid cascade may be partially associated with the inhibitory effect of TJN-101 on liver injuries.
75: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1990 Feb;12(1):42-5.
[Deuteration of dimethyl 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (BDD): a remedy for chronic hepatitis]
Tong Q. PUMC Hospital , Beijing .
A new antihepatitic drug, BDD (I), which is very active and powerful especially in lowering elevated SGPT levels, has been previously discovered during the systematic study of Schisandra chinensis. In order to study the metabolism of this new antihepatic drug, deuterated BDD was prepared according to the following method. BDD lg, sodium chloroplatinate 193 mg, deuterium oxide 16ml, acetic anhydride 30ml, and acetyl chloride 0.4 ml were well mixed in a sealed ampoule and heated to 120-130 degrees C for 12h. The mixture was then poured into water. The precipitate (0.86g) contained the deuterated acid (IIa, IIb) of BDD. After esterification with methanol, a mixture (m.p. 150-153 degrees C) of mono- and di-deuterated BDD was obtained. Molecular clustering, as determined by GC/MS, showed that the product consisted of mono-deutero-BDD (IIIa) (m/e419) and dideutero-BDD (IIIb) (m/e420) in the ratio of 1:1.3.
76: Yao Xue Xue Bao. 1990;25(1):49-53.
[Determination of the active ingredients in Chinese drug wuweizi (Schisandra chinensis) by TLC-densitometry]
Wang K, Tong YY. Institute of Materia Medica , Chinese Academy of Medical Sciences, Beijing .
A method of TLC densitometry was developed to determine the active ingredients (Wuweizisu A, B, C; Wuweizichun A, B; Wuweizi ester and schisanhenol) in Schisandra kernels. The samples were extracted with hexane (3 X 5 ml) for 8, 4 and 4 h respectively. The hexane extract was evaporated to dryness and then dissolved in 1 ml of methanol. Standard solutions and sample solutions were spotted on a silica gel GF254 plate, and developed with toluene-ethyl acetate (9:1) for 18 cm (for Wuweizisu A, B, C) and with toluene-ethyl acetate (4:6) for 18 cm (for Wuweizichun A, B, Wuweizi ester and schisanhenol). On examining the chromatogram under UV light the ingredients appeared as dark spots. A Shimadzu TLC model 910 was used for scanning at lambda s 260 nm and lambda R 350 nm by reflection mode. Linear calibration curves were obtained for the 7 constituents in the range of 1-5 micrograms. The average recoveries of the 7 constituents were 92.4-101.6%; the variation coefficients were 1.62-5.28%. The spots were stable for more than 24 h. This method is sufficiently simple, rapid and accurate for routine analysis.
77: Chem Pharm Bull ( Tokyo ). 1990 Jan;38(1):136-41.
Studies on the metabolism of gomisin A (TJN-101). II. Structure determination of biliary and urinary metabolites in rat.
Ikeya Y. Research Institute for Biology & Chemistry, Tsumura & Co., Ibaraki , Japan .
After oral administration of gomisin A (1) to rats, the bile and urine were collected and treated with beta-glucuronidase and arylsulfatase. Seven metabolites, met B (2), met A-III (3), met E (4), met D (5), met F (6), met G (7), and met H (8) were isolated from the bile treated with the enzymes. Eight metabolites 2-8, and met A-II (9) were isolated from the urine treated with the enzymes. A major metabolite 2, and two minor metabolites 3 and 9 were identified as met B, met A-III, and met A-II, respectively, which are oxidative products of 1 formed by rat liver S9 mix. The structures of five new metabolites 4-7, and 8 were determined on the basis of chemical and spectral studies.
78: Yao Xue Xue Bao. 1990;25(3):215-9.
[Bioavailability studies on the preparations of biphenyl dimethyl dicarboxylate(DDB)]
Gu SJ. Institute of Materia Medica , Chinese Academy of Medical Sciences, Beijing .
Since the bioavailability of the suspension and the tablet of DDB given orally is only 20-30%, we have prepared four kinds of DDB solid dispersion preparations (DDB pilule I with polyethylene glycol 6000 as the vehicle, DDB pilule II with polyethylene glycol 6000 and absorption accelerator as the vehicle, capsule of DDB-urea fusing mixture and DDB-polyvinyl pyrrolidone coprecipitate), and the bioavailability of these preparations were studied in rabbits, rats and human volunteers by HPLC method. All four preparations showed better absorption than the DDB tablet, and the area under serum DDB concentration-time curve of pilule II was 19 fold that of the tablet in rabbits, meaning that the absorption of pilule II is the best of the four preparations. After administration of the four solid dispersion preparations, the fecal excretion of DDB were all lower than the tablet in both animals and human volunteers. The protective action of pilule II against CCl4 hepatotoxicity was about six times stronger than that of the suspensions. Therefore, there are good reasons to use DDB pilule II instead of the tablets of suspension in the clinic.
79: Yao Xue Xue Bao. 1990;25(2):110-22.
[Mass spectrometric studies on dibenzocyclooctadiene lignan compounds from Schisandraceae plants]
Zhai HB. Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing .
Mass spectrometric studies on fragmentation patterns of 23 dibenzocyclooctadiene lignan compounds isolated from Schisandraceae plants, such as schisandra A (1), were carried out by using low and high-resolution mass spectrometric techniques and metastable ion analyses. The main mass spectral characteristics were summarized to provide a sound basis for further researches on Schisandraceae plants and for structural elucidation of similar new compounds.
80: Zhongguo Zhong Yao Za Zhi. 1989 Oct;14(10):611-4, 639-40.
[Determination of Lignans in the fruits of Schisandra chinensis (Trucz.) Baill. and S. Sphenanthern Rehd. et Wils. using HPLC and their chromatograms]
Tong YY, Song WZ.
The lignans contained in the fruits of Schisandra chinensis and S. sphenanthern were determined by HPLC. Their chromatograms are different. 7 samples of S. chinensis from 6 habitats contain the same lignans, but in different quantity, while 16 samples of S. sphensnthern contain lignans different both in quality and quantity.
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81: Planta Med. 1989 Feb;55(1):13-7.
The effect of gomisin A on immunologic liver injury in mice.
Nagai H, Yakuo I, Aoki M.
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The hepatoprotective effect of Gomisin A (TJN-101), which is a lignan compound isolated from Schizandra fruits, was studied on three immunologic liver injury models in mice. The first liver injury model was produced by the injection of anti-basic liver protein (BLP) antibody into DBA/2 mice which had been previously immunized with rabbit IgG (RGG). Other models were effected by injection of anti-liver specific protein (LSP) antibody into DBA/2 mice or by the injection of bacterial lipopolysaccharide (LPS) into ddY mice pretreated with Corynebacterium parvum (C. parvum). TJN-101 inhibited the elevation of transaminase (GOT and GPT) activities and showed the tendency to inhibit the histopathological changes of the liver in all models. Moreover, TJN-101 inhibited deoxycholic acid-induced release of transaminase from cultured rat hepatocytes in vitro, but did not affect the formation of hemolytic plaque forming cells in immunized mice spleens and hemolytic activity of guinea pig complement in immunohemolysis reaction. These results, therefore, suggested that the hepatoprotective effect of TJN-101 could be related to the protecting effect of hepatocyte plasma membrane rather than the inhibiting effects of the antibody formation and complement activity. |
82: Yao Xue Xue Bao. 1989 Jan;24(1):1-4.
[The effect of biphenyl dimethyl dicarboxylate (DDB) on the fluidity of human erythrocyte membrane]
Chen L, Chen WW.
This paper deals with the effects of DDB on human RBC membrane fluidity as reflected by changes in the phase transition temperature and microviscosity monitored by ANS, NPN and DPH. The results showed that DDB decreased the fluidity of the shallow layer (ANS as probe), but increased the fluidity of the middle layer (NPN as probe) and deeper layer (DPH as probe). In addition, the drug was found to inhibit the hemolysis induced by MDA.
83: Yao Xue Xue Bao. 1989;24(11):859-64.
[The dissolution rate and physical dispersion state of preparations of biphenyl dimethyl dicarboxylate (DDB)]
Gu SJ, Gao WW, Qiao PX, Wang AG, Qiang ZY.
DDB is poorly soluble in water. The solid dispersions of DDB with easily soluble carriers such as polyethylene glycol 6000 (PEG 6000), polyvinyl pyrrolidone (PVP) and urea were prepared by melting and solvent methods. The two DDB-PEG 6000 systems are thermodynamically stable interstitial solid solutions. The DDB-PVP system is an amorphous precipitate and the DDB-urea system is a simple eutectic physical mixture judged by X-ray diffraction and thermal analysis methods. The dissolution rate of DDB-PEG 6000 pilule and two kinds of DDB tablets were determined. The dissolution rate of DDB-PEG 6000 pilule was found to be faster. The physical dispersion state is an important factor in relation to the dissolution rate of DDB preparations.
84: Nippon Yakurigaku Zasshi. 1988 Apr;91(4):237-44.
[Effect of gomisin A (TJN-101), a lignan compound isolated from Schisandra fruits, on liver function in rats]
Takeda S. Tsumura Research Institute for Pharmacology, Ibaraki , Japan .
TJN-101 [+)-(6S, 7S, R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy- 6,7-dimethyl-10,11-methylenedioxy-6-dibenzo [a, c] cyclooctenol) is one of the lignan compounds isolated from Schisandra fruits. When TJN-101 was administered orally at the doses of 3-100 mg/kg/day for 4 days, bile secretion, hepatic excretion of dye or hepatic hemodynamics 24 hr after the last dose was investigated in comparison with the phenobarbital (100 mg/kg/day)-treated group. Bile flow was dose-dependently increased; in contrast, biliary concentration of bile acids was decreased in TJN-101 (30 and 100 mg/kg/day)-treated groups. Similar changes were also observed in the phenobarbital-treated group. These results suggested that the enhancement of bile secretion caused by TJN-101 or phenobarbital was due to an increase of a bile acid-independent fraction. In the bromosulfophthalein (BSP) clearance test for liver function, both TJN-101 (30 and 100 mg/kg/day) and phenobarbital accelerated the disappearance from the blood and biliary excretion of BSP. Hepatic hemodynamics was examined by the hydrogen clearance method and measurement of liver wet and dry weight. Liver blood flow tended to increase in the TJN-101 (10-100 mg/kg/day) or phenobarbital-treated group. On the other hand, TJN-101 (3-100 mg/kg/day) or phenobarbital hardly altered the water content of the liver. These results suggested that the liver enlargement caused by both compounds was not accompanied with hepatic edema and that the enhancement of bile secretion or hepatic excretion of BSP might be related to an increase of liver blood flow.
85: Nippon Yakurigaku Zasshi. 1987 Jul;90(1):51-65.
[Effects of TJN-101, a lignan compound isolated from Schisandra fruits, on liver fibrosis and on liver regeneration after partial hepatectomy in rats with chronic liver injury induced by CCl4]
Takeda S, Kase Y, Arai I,. Tsumura Research Institute for Pharmacology, Ibaraki , Japan .
TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11-methylenedioxy-6-dibenzo[a,c]cyclooctenol) is one of the lignan compounds isolated from Schisandra fruits. 1) Effect of TJN-101 on liver fibrosis was investigated in rats which were injected with CCl4 (1 ml/kg) subcutaneously twice a week for 12 weeks. TJN-101 was given orally at the dose of 10 or 30 mg/kg/day for 6 or 3 weeks beginning on the 6th or 9th week after the start of CCl4-intoxication, respectively. The elevations of serum transaminase activities and the increase of liver 4-hydroxyproline content were observed depending on the period of CCl4-intoxication. These changes were marked on the 9th and 12th weeks after. In the histopathological study, the degenerative fatty change on the 6th week after and the formation of pseudolobule caused by fibrosis proliferation on the 9th or 12th week after were mainly observed. When rats were treated with TJN-101, the abnormalities in biochemical parameters and the fibrosis proliferation caused by CCl4-intoxication were improved. 2) Chronic liver injury was induced by the treatment with CCl4 (1 ml/kg) subcutaneously twice a week for 10 weeks to investigate the effect of TJN-101 on liver regeneration after partial hepatectomy. TJN-101, which was given orally at the dose of 10, 30 or 100 mg/kg/day for 6 days from the 1st day after partial hepatectomy, dose-dependently increased the liver regeneration rate and improved the serum BSP retention rate. These results suggest that TJN-101 suppresses the fibrosis proliferation and accelerates both the liver regeneration and the recovery of liver function after partial hepatectomy in chronic liver injury.
86: Jpn J Pharmacol. 1987 Jun;44(2):179-85.
Inhibitory effect of TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11- methylenedioxy-6-dibenzo[a,c]cyclooctenol) on immunologically induced liver injuries.
Ohkura Y. Third Department of Internal Medicine, Osaka City University Medical School , Japan .
TJN-101, which is a lignan component isolated from schisandra fruits, inhibits hepatotoxic chemicals-induced liver injuries. In this study, effects of TJN-101 on immunologically induced liver injuries were investigated in vivo and in vitro. When a small dose of lipopolysaccharide was injected into mice previously injected with heat-killed Propionibacterium acnes, most of the animals died with acute hepatic failure which was produced by cytotoxic factors from activated adherent cells, and liver cells were injured by antibody-dependent cell-mediated cytotoxic (ADCC) reaction or activated macrophages in vitro. TJN-101 reduced the mortality of the mice with acute hepatic failure dose-dependently. Histologically, necrosis was suppressed by the treatment of TJN-101, but infiltration of non-specific inflammatory cells was not. TJN-101 inhibited the isolated liver cell injuries induced by ADCC reaction or activated macrophages in vitro. These results suggest that TJN-101 can be markedly protective against immunological liver injuries. |
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87: Muscle Nerve. 1987 Jun;10(5):391-6.
The effect of DDB on dystrophic hamsters: an in vivo and in vitro study.
Shen DG, Araki M, Higuchi I.
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| Dimethyl-4, 4'-dimethoxy-5, 6, 5'-6'-dimethylenedioxybiphenyl-2, 2'-dicarboxylate (DDB) is a synthetic analogue of Schizandrin C, an active compound isolated from a Chinese herb, Fructus schizandrae. We administered this compound to dystrophic hamsters in vivo for 31 days. This led to a 61% reduction of the calcium content, an 86% reduction of the area of calcium deposits, and a 52% reduction of the area of necrosis of cardiac muscle. However, skeletal muscle necrosis was not significantly improved. No clear change in plasma creatine kinase (CK) was observed. In an in vitro incubation study, the rate of CK release and tetanus tension of the extensor digitorum longus muscle of dystrophic hamsters were not substantially changed by the addition of DDB. This study suggests that DDB has some effect on cardiac necrosis, and that it might be useful for treatment of the cardiac involvement in patients with muscular dystrophy or other conditions with accompaning Ca accumulation. |
88: Nippon Yakurigaku Zasshi. 1986 Oct;88(4):321-30.
[Effects of TJN-101 ((+)-(6s,7s,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy-6,7 -dimethyl-10,11-methylenedioxy-6-dibenzo [a,c] cyclooctenol) on liver regeneration after partial hepatectomy, and on regional hepatic blood flow and fine structure of the liver in normal rats]
Takeda S, Kase Y, Arai I.
Effects of TJN-101, one of the components isolated from Schizandra fruits, on liver regeneration after partial hepatectomy, and on regional hepatic blood flow and fine structure of the liver were investigated in normal rats. TJN-101, which was administered orally at the doses of 10, 30 and 100 mg/kg/day for 4 days after partial hepatectomy, increased the regeneration rate of the liver and improved the serum retention rate of BSP which had been dose-dependently decreased after the operation. Elevation of serum protein to control levels, elevation of serum LCAT activity, decrease in plasma insulin and increase in plasma glucagon were all dose-dependent responses to TJN-101. The mitotic index on the 5th day after the operation was hardly influenced by TJN-101. Regional hepatic blood flow was increased after intraduodenal administration of TJN-101 (30 and 100 mg/kg). Ultrastructural studies of liver tissue using the transmission electron microscope revealed that TJN-101 stimulated an increase in rough and smooth endoplasmic reticulum in the groups receiving 100 and 300 mg/kg/day. These results suggest that TJN-101 accelerates both the proliferation of hepatocytes and the recovery of liver function after partial hepatectomy and increases hepatic blood flow. It is also thought that the liver enlargement caused by repeated administration of TJN-101 is associated with the proliferation of endoplasmic reticulum.
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89: Food Chem Toxicol. 1986 Sep;24(9):903-12.
Effects of dietary Schizandra chinensis, brussels sprouts and Illicium verum extracts on carcinogen metabolism systems in mouse liver.
Hendrich S, Bjeldanes LF.
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| Ethanol extracts of Brussels sprouts (BRX), Schizandra chinensis (SZX) or Illicium verum (IVX) were added to a semi-purified basal diet and fed to adult male and female C57B1/6 mice for 14 and 10 days, respectively. Other groups received the unsupplemented basal diet or a mouse chow. Liver fractions were prepared from these mice to investigate the effects of the diets on the enzyme systems involved in benzo[a]pyrene (BP) and aflatoxin B1 (AFB1) metabolism. The effects of the microsomal or cytosolic liver fractions on the in vitro mutagenicity of BP and AFB1 and on the DNA binding of AFB1 were also studied. There were several apparently sex-related differences in the responses of the monooxygenase system components measured. In males, cytochrome P-450 levels were significantly increased only in the chow group, while significant increases in both 7-ethoxycoumarin O-deethylase (ECD) and aryl hydrocarbon hydroxylase (AHH) activities were seen only in the SZX group. In females, cytochrome P-450 levels were significantly increased in both the BRX and SZX groups, whereas AHH activity was significantly increased only in the chow and BRX groups and ECD activity was increased in the SZX and IVX groups. Microsomal epoxide hydratase (EH) was induced in males in the SZX and IVX groups and in females only in the SZX group, while cytosolic EH was significantly increased only in IVX males. Diet-induced changes in monooxygenase activities were found to be the best indicators of changes in microsome-mediated BP mutagenesis and AFB1 mutagenesis and binding to DNA in vitro, with a direct correlation between high AHH and/or ECD activities and the levels of mutagenic response to BP or AFB1 in the Ames assay and of DNA binding of AFB1. |
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90: Food Chem Toxicol. 1985 Jan;23(1):57-65.
The effects of dietary brussels sprouts and Schizandra chinensis on the xenobiotic-metabolizing enzymes of the rat small intestine.
Salbe AD, Bjeldanes LF.
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| After an initial equilibration period of 7 days on a semi-synthetic basal diet, male Sprague-Dawley rats were fed for 2 wk on either the basal diet (controls), the basal diet containing 5% Schizandra chinensis or 25% Brussels sprouts, or on rat chow. One group of chow-fed rats was pretreated with 20 mg 3-methylcholanthrene (3-MC)/kg body weight, 24 hr before they were killed. Microsomal and cytosolic fractions were prepared from small intestine mucosa. Microsomes were assayed for cytochrome P-450, aryl hydrocarbon hydroxylase (AHH), ethoxycoumarin O-deethylase (ECD) and epoxide hydrolase (EH) activities, and for metabolism of benzo[a]pyrene (BaP), Cytosols were assayed for glutathione S-transferase (GST) activity. The largest increase in intestinal mixed-function oxidase activity over levels in the controls was seen in the 3-MC-treated group. However, EH and GST activities in these animals were not significantly increased. Increases in cytochrome P-450 levels and significant increases in AHH, ECD, EH and GST activities occurred in the rats fed Brussels sprouts. Rats in the S. chinensis group showed inhibition of AHH activity relative to controls, but increased activity of ECD, EH and GST. In the rats fed chow there were significant increases in the activities of all the enzymes assayed except GST. The percentage conversion of BaP to metabolites reflected the results of the AHH assay and the groups were ranked in the following order: 3-MC greater than Brussels sprouts greater than rat chow greater than basal diet greater than S. chinensis. The profile of BaP metabolites showed a larger proportion of the BaP diols and 3-hydroxybenzo[a]pyrene, and a smaller proportion of BaP-4,5-epoxide and the BaP quinones, for the Brussels sprouts- and S. chinensis-fed groups. The significance of these results is discussed in regard to the role of the small intestine as a mediator of toxicity induced by ingested chemicals. |
91: Sci Sin [B]. 1983 Dec;26(12):1291-303.
Studies on antihepatitic drugs. Total synthesis of (+/-)schizandrin C and its analogs.
Xie JX, Zhou J, Zhang CZ, Yang JH, Chen JX.
This paper reports the total synthesis of (+/-) schizandrin, C, namely 5,6,7,8-tetrahydro-1, 12-dimethoxy-2, 3, 10, 11-bismethylenedioxy-6, 7-cis-dimethyldibenzo (a, c) cyclooctene (12B), a new active SGPT lowering principle isolated from the Chinese medical plant Schizandra chinensis, and its 6, 7-trans-dimethyl isomer (16B). We also synthesized two more isomers, namely 5, 6, 7, 8-tetrahydro-3, 10-dimethoxy-1, 2, 11, 12-bismethylenedioxy-6, and 7-cis-(and trans-) dimethyldibenzo (a, c) cyclooctene (12A and 16A). The NMR, UV and mass spectra of these four isomers are discussed. IR (in chloroform), UV, NMR and MS of synthetic schizandrin C (12B) are identical with those of the natural compound. |
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92: Food Chem Toxicol. 1983 Aug;21(4):479-86.
Effects of dietary cabbage, Brussels sprouts, Illicium verum, Schizandra chinensis and alfalfa on the benzo[alpha]pyrene metabolic system in mouse liver.
Hendrich S, Bjeldanes LF.
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| Male C57B16 mice were fed on diets containing either 20% cabbage, 20% Brussels sprouts, 20% alfalfa, 5% Schizandra chinensis or 5% Illicium verum (two Chinese medicinal herbs) or on a chow or purified basal diet for 14 days after a 1-wk equilibration period on the basal diet. Liver microsomal fractions were assayed for cytochrome P-450 content, aryl hydrocarbon hydroxylase (AHH) and epoxide hydrolase (EH). Liver microsome-mediated benzo[a]pyrene (BP) metabolism (with and without an EH inhibitor, 1,2-epoxy-3,3,3-trichloropropane) was analysed by HPLC. Liver weights of the animals fed on Brussels sprouts and I. verum were significantly increased compared with those of the animals fed on basal diets. S. chinensis induced a 3-fold increase in cytochrome P-450 (P less than 0.05). Although P-450 induction in the other groups was as high as 1.8-fold (for chow), statistical significance was not established. Chow induced AHH activity 2.2-fold (P less than 0.05), while S. chinensis and alfalfa induced 1.6-fold and 1.7-fold increases, respectively, in AHH activity, although neither increase was statistically significant. EH was stimulated significantly in the following order: I. verum (2.1-fold) greater than chow (1.7-fold) greater than S. chinensis (1.6-fold) greater than Brussels sprouts (1.4-fold). Total levels of BP metabolism and phenol II (primarily 3-hydroxybenzo[a]pyrene) formation were closely associated for each dietary treatment. Total BP metabolism was significantly increased (2.1-fold) in the chow-fed group and increased 1.6-fold in the S. chinensis group (P greater than 0.05). No increase was seen with the other diets. Phenol II formation relative to total metabolites was significantly increased for the S. chinensis and I. verum groups compared to the basal group. Diet-related variations in phenol production relative to total metabolism were eliminated by addition of the EH inhibitor to the incubation media. |
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93: Chem Biol Interact. 1982 Jul 15;41(1):39-47.
Pharmacological properties of Dibenzo[a,c]cyclooctene derivatives isolated from Fructus Schizandrae Chinensis III. Inhibitory effects on carbon tetrachloride-induced lipid peroxidation, metabolism and covalent binding of carbon tetrachloride to lipids.
Liu KT, Lesca P.
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| Fructus Schizandrae, a traditional Chinese tonic, has been shown to lower the elevated serum glutamic pyruvic transaminase (SGPT) levels of patients with chronic viral hepatitis and several of its components decrease the hepatotoxicity of carbon tetrachloride (CCl4) in animals. This paper deals with the mechanism of protection against CCl4-hepatotoxicity of these compounds as well as of DDB, a synthetic analogue of Schizandrin (Sin) C. Of the seven components, Sin B and C, Schizandrol (Sol) B, Schizandrer (Ser) A and B, as well as dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-biphenyl-2,2'-dicarboxylate (DDB) were shown to inhibit CCl4-induced lipid peroxidation and [14C]Cl4 covalent binding to lipids of liver microsomes from phenobarbital(PB)-treated mice. The compounds also decreased carbon monoxide (CO) production and cofactor (NADPH, oxygen) utilization during CCl4 metabolization by liver microsomes. It may be postulated, therefore, that the hepatoprotective effect of certain components isolated from Fructus Schizandrae as well as DDB is due to their inhibitory effect on CCl4-induced lipid peroxidation and the binding of CCl4-metabolites to lipids of liver microsomes. |
94: Chem Biol Interact. 1982 Apr;39(3):301-14.
Pharmacological properties of dibenzo[a,c]cyclooctene derivatives isolated from Fructus Schizandrae chinensis. I. Interaction with rat liver cytochrome P-450 and inhibition of xenobiotic metabolism and mutagenicity.
Liu KT, Lesca P.
Seven compounds isolated from Fructus Schizandrae chinensis, a traditional Chinese tonic, which is also able to increase liver lesions by hepatoxic chemicals, are named Schizandrin (Sin) A, B and C, Schizandrol (Sol) A and B and Schizandrer (Ser) A and B. They are dibenzo[a,c]cyclooctene derivatives. Dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-biphenyl-2,2'-dicarboxylate (DDB) is an intermediate for synthesizing Sin C. The interactions of these compounds with rat liver microsomes in vitro have been investigated. Sol A and Sol B gave type I difference spectrum, the other six compounds gave 'reverse type I' difference spectrum. When Schizandrins or DDB were incubated with NADPH-reduced microsomes, Sin B, Sin C, Sol B, Ser A and Ser B generated dual Soret peaks of 455--460 nm and 425--430 nm, the other three compounds caused a difference spectrum without 455 nm peak. All these compounds more or less inhibit liver microsomal hydroxylation of benzo[a]pyrene (BP) demethylation of aminopyrine. Sin B, Sol B and DDB decreased mutagenicity of BP in Ames test. |
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95: Chem Biol Interact. 1982 Apr;39(3):315-30.
Pharmacological properties of dibenzo[a,c]cyclooctene derivatives isolated from Fructus Schizandrae chinensis. II. Induction of phenobarbital-like hepatic monooxygenases.
Liu KT, Cresteil T, Columelli S, Lesca P.
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| Schizandrin (Sin) A, B and C, Schizandrol (Sol) A and B and Schizandrer (Ser) A and B were isolated from Fructus Schizandrae chinensis, a traditional Chinese tonic. These components are the derivatives of dibenzo[a,c]cylooctene. Dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-biphenyl-2,2'-dicarboxylate (DDB) is an intermediate for synthesizing Sin C. The effect of these compounds on rat liver microsomal monooxygenases and epoxide hydrolase has been studied. Among these compounds, Sin B, Sin C, Sol B and DDB significantly increased rat liver cytochrome P-450 concentration, NADPH-cytochrome c reductase, benzphetamine and aminopyrene demethylase activities. The four compounds also markedly stimulated proliferation of smooth endoplasmic reticulum of liver cells. Metyrapone (1 mM) inhibited to a same extent (about 50%) the activity of aminopyrene demethylase of microsomes from rats treated by Sin B, Sin C, Sol B, DDB and phenobarbital (PB). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of liver microsomal preparations showed that Sin B and Sol B induce a major protein band of P-450 similar to that induced by PB. In addition, the effect of Sin B-, Sol B- and DDB-treated rat liver microsomes on [G-3H]-benzo[a]pyrene (BP) metabolism and covalent binding of reactive metabolites to DNA, in vitro, resembles that of PB. Dual induction of rats by Sol B and BP decreased mutagenicity of BP. |
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96: Am J Chin Med. 1981 Winter;9(4):277-84.
Screening of the wormicidal Chinese raw drugs on Clonorchis sinensis.
Rhee JK, Woo KJ, Baek BK, Ahn BJ.
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| The wormicidal effect on Clonorchis sinensis in boiled water extracts of 223 species (vegetable origin 206, animal origin 10, mineral origin 7) of raw drugs prescribed in Oriental medicine was observed in vitro. The wormicidal substances were detected from 31 of the above-mentioned species. The wormicidal substances extracted from Platycodon grandiflorum (radix), Schizandra chinensis (fruit), Polygala tenuifolia (herb) and Aster tataricus (radix) were most effective. Those from Smilax glabra (radix), Pueraria thunbergiana (flower, radix), Polygala tenuifolia (radix), Scutellaria baicalensis (radix), Prunus mume (fruit), Glycyrrhiza uralensis (radix), Angelica koreana (radix), Phytolacca esculenta (radix) and Cyrtomium fortunei (rhizoma) were effective. The rest of the raw drugs were less effective. |
97: Sci Sin. 1976 Mar-Apr;19(2):276-90.
Studies of Fructus schizandrae. IV. Isolation and determination of the active compounds (in lowering high SGPT levels) of Schizandra chinensis Baill.
Yan-yong C, Zeng-bao S, Lian-niang L.
The alcoholic extracts of the kernels of Schizandra chinensis Baill have been reported to be capable of lowering elevated SGPT levels in mice induced by CCl4 and inhibiting the central nervous system. Seven pharmacological active compounds have been isolated from the alcoholic extracts by column chromatography. Five of them are identified as wuweizisu C (I), wuweizisu B (II), wuweizisu A (III), wuweizichun B (IV) and wuweizichun A (V). They are all derivatives of the dibenzo (a, c) cyclooctene system, among which compounds I and IV have hitherto not been reported in literature. Ozonolysis of III and subsequent oxidation with H2O2 yields meso-3,4-dimethyladipic acid. Pyrolytic syn-elimination of V acetate and oxidation of the resultant olefin (V-4) affords a diketone (V-5) with molecular weight of 446. According to these results and based on the NMR spectra, the two methyl groups at C-6 and C-7 of compound I--V must be cis-oriented. |
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