Article

Effects of unprocessed versus vinegar-processed Schisandra chinensis on the activity and mRNA expression of CYP1A2, CYP2E1 and CYP3A4 enzymes in rats

College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046,PR China.
Journal of ethnopharmacology (Impact Factor: 3). 04/2013; 146(3):734–743. DOI: 10.1016/j.jep.2013.01.028

ABSTRACT

Ethnopharmacological relevanceSchisandra chinensis (SC) is a well-known traditional Chinese herbal medicine that has been used in clinical practices for thousands of years. However, the differences between the effects of unprocessed and vinegar-processed Schisandra chinensis (VSC) on cytochrome P450 (CYP450) activities are poorly understood.Aim of the studyTo evaluate the differences between processed and unprocessed SC on the metabolism of CYP1A2, CYP2E1 and CYP3A4 substrates in rats using a cocktail method based on a developed and validated HPLC method. We also investigate the influence of processing on the levels of CYP mRNA.Materials and methodsThree probe substrates (theophylline, dapsone and chlorzoxazone) were delivered simultaneously into rats treated with single or multiple doses of processed or unprocessed SC extract. The plasma concentrations of the three probes were profiled by HPLC, and their corresponding pharmacokinetic parameters were calculated. Real-time RT-PCR was performed to determine the effects of processed and unprocessed SC on the mRNA expression of CYP1A2, CYP2E1 and CYP3A4 in the liver.ResultsTreatment with single or multiple doses of either extract of SC induced CYP3A4 enzyme activity and inhibited CYP1A2 enzyme activity in rats. Furthermore, the inhibitory effect of SC was more potent after vinegar processing than without vinegar processing. CYP2E1 enzyme activity was induced after treatment with a single dose but was inhibited after multiple doses. The mRNA expression results were in accordance with the pharmacokinetic results.Conclusions
These results provide useful scientific data for the safe clinical application of either extract of SC in combination with other drugs, which should lack the side effects induced by other herb–drug interactions.

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    • "More recently, Su et al. reported that the unprocessed or vinegar-processed Schisandra chinensis extract induced CYP3A4 enzyme activity and inhibited CYP1A2 enzyme activity in rats after single or multiple dosing treatments. In addition, CYP2E1 enzyme activity was induced after treatment with a single dose but was inhibited after multiple doses (Su et al., 2013). Based on these discrepant results, more studies are required to clarify the effects of SC components on specific hepatic CYPs and give more insight into the guideline of rational administration for using this herbal medicine. "
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    ABSTRACT: Ethnopharmacological relevance: Schisandra chinensis (SC), officially listed as a sedative and tonic in the Chinese Pharmacopoeia, has been used as a common component in various prescriptions in Traditional Chinese Medicine (TCM) and more recently in western medicine for its antihepatotoxic effect. To assess the possible herb-drug interaction, effects of SC extracts on hepatic cytochrome P450 (P450, CYP) enzymes were studied. Material and methods: Effects of SC extracts on rat hepatic CYP450 enzymes in vitro and in vivo were investigated by probe substrates method, real-time RT-PCR assay and Western blotting analysis. Furthermore, the effects of SC alcoholic extract on the PK of four SC lignans and the drugs possibly co-administrated in vivo were studied in male Sprague-Dawley rat. Results: SC aqueous extract and alcoholic extract showed significant inhibitory effect on the activities of rat liver microsomal CYP1A2, 2C6, 2C11, 2D2, 2E1 and 3A1/2 in vitro. Multiple administrations of SC aqueous extract (1.5g/kg, qd×7d) and alcoholic extract (1.5g/kg, qd×7d) increased the activities, mRNA and protein expressions of CYP2E1 and CYP3A1/2, and meanwhile, inhibited the activities and mRNA expression of CYP2D2 in vivo. The in vivo metabolism of four SC lignans, such as schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, and chlorzoxazone was significantly accelerated, exhibited by the reduced AUC and increased CLz/F, by 7-day pretreatment with SC alcoholic extract. However, both single and multiple dosing treatments of SC alcoholic extract remarkably decreased the in vivo metabolism of tacrolimus indicated by the enhanced AUC (7-12 fold) and elevated Cmax (10 fold). Conclusion: These results revealed that the SC extracts exhibited multifaceted effects on rat hepatic CYP450 enzymes. Herb-drug interaction should be paid intense attention between SC components and drugs metabolized by different CYP450 enzymes.
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    ABSTRACT: Aescin, the main active component found in extracts of horse chestnut (Aesculus hippocastanum) seed a traditional medicinal herb, is a mixture of triterpene saponins. It has been shown to be effective in inflammatory, chronic venous and edematous treatment conditions in vitro and in vivo, and is broadly used to treat chronic venous insufficiency. The purpose of this study was to find out whether aescin influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9, CYP2E1 and CYP3A4) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied. A cocktail solution at a dose of 5mL/kg, which contained phenacetin (20mg/kg), tolbutamide (5mg/kg), chlorzoxazone (20mg/kg) and midazolam (10mg/kg), was given as oral administration to rats treated with a single dose or multiple doses of intravenous aescin via the caudal vein. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time RT-PCR was performed to determine the effects of aescin on the mRNA expression of CYP1A2, CYP2C9, CYP2E1 and CYP3A4 in rat liver. Treatment with a single dose or multiple doses of aescin had inductive effects on rat CYP1A2, while CYP2C9 and CYP3A4 enzyme activities were inhibited. Moreover, aescin has no inductive or inhibitory effect on the activity of CYP2E1. The mRNA expression results were in accordance with the pharmacokinetic results. Aescin can either inhibit or induce activities of CYP1A2, CYP2C9 and CYP3A4. Therefore, caution is needed when aescin is co-administration with some CYP1A2, CYP2C9 or CYP3A4 substrates in clinic, which may result in treatment failure and herb-drug interactions.
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    ABSTRACT: In traditional therapy with Chinese medicine, hydroxysafflor yellow A (HSYA), a main active component isolated from the dried flower of Carthamus tinctorius L., is the principal efficiency ingredient of Safflor Yellow Injection. Now HSYA has been demonstrated to have good pharmacological activities of antioxidation, myocardial and cerebral protective and neuroprotective effects. The purpose of this study was to find out whether HSYA influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, CYP2D4 and CYP3A1) by using cocktail probe drugs in vivo; the influence on the levels of CYP mRNA was also studied. A cocktail solution at a dose of 5mL/kg, which contained phenacetin (20mg/kg), tolbutamide (5mg/kg), dextromethorphan (20mg/kg) and midazolam (10mg/kg), was given as oral administration to rats treated with short or long period of intravenous HSYA via the caudal vein. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. In addition, real-time RT-PCR was performed to determine the effect of HSYA on the mRNA expression of CYP1A2, CYP2C11, CYP2D4 and CYP3A1 in rat liver. HSYA had significant inhibition effects on CYP1A2 and CYP2C11 in rats as oriented from the pharmacokinetic profiles of the probe drugs. Furthermore, HSYA had no effects on rat CYP2D4. However, CYP3A1 enzyme activity was induced by HSYA. The mRNA expression results were in accordance with the pharmacokinetic results. HSYA can either inhibit or induce activities of CYP1A2, CYP2C11 and CYP3A1. Therefore, co-administration of some CYP substrates with HSYA may need dose adjustment to avoid an undesirable herb-drug interaction.
    No preview · Article · Dec 2013 · Journal of ethnopharmacology
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