Effects of short-term and long-term pretreatment of Schisandra lignans on regulating hepatic and intestinal CYP3A in rats.
ABSTRACT This study aimed to evaluate the effects of Schisandra lignan extract (SLE) with short- and long-term pretreatment on regulating rat hepatic and intestinal CYP3A for a comprehensive evaluation of metabolism-based herb-drug interactions. Inhibitory effects of SLE and its major components on rat CYP3A were confirmed in both hepatic and intestinal microsomal incubation systems. After a single dose of SLE pretreatment, higher C(max) and area under the concentration-time curves from zero to infinity (AUC(0-infinity)) values were observed for intragastric midazolam (MDZ), whereas those for the intravenous MDZ were little changed. The mechanism-based inhibition of SLE toward CYP3A was further confirmed in vivo, characterized with a recovery half-life of 38 h. In contrast, SLE long-term treatment enhanced both hepatic (2.5-fold) and intestinal (4.0-fold) CYP3A protein expression and promoted the in vivo clearance of MDZ. When MDZ was coadministered with SLE after a consecutive long-term treatment, the AUC(0-infinity) value of MDZ was still lower than that of the control group, suggesting a much stronger inducing than inhibiting effect of SLE toward CYP3A. Furthermore, the intragastric administration of SLE exhibited a more intensive regulating effect toward intestinal than hepatic CYP3A, which could be partially explained by the relatively high exposures of lignans in the intestine. In conclusion, this study provides a comprehensive map for showing the complicated effects of SLE and its components on regulating rat CYP3A. The important findings are that SLE possesses a much stronger inducing than inhibiting effect on CYP3A, as well as a more intensive regulating effect on intestinal than hepatic CYP3A.
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ABSTRACT: Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pre-treatment significantly attenuated the increases in ALT and AST activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial GSH in a dose-dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI-GSH. A molecular docking model also predicted that SolB has potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and anti-apoptotic related proteins such as CCND1, PCNA and BCL-2. This study demonstrated that SolB exhibits a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA and BCL-2 to promote liver regeneration.Toxicological Sciences 10/2014; · 4.48 Impact Factor
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ABSTRACT: Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contributing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concentration-dependently up-regulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N-4 cells. Data from western blotting and QT-PCR showed that induction of CYP3A4 activity was associated with up-regulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid-induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK-, PKC-, and NF-κB-dependent pathways, whereas that by palmitic acid was possibly associated with the PKC-dependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.Journal of Pharmacological Sciences 01/2014; 124(4):433-44. · 2.11 Impact Factor
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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.Journal of ethnopharmacology 04/2013; 146(3):734–743. · 2.32 Impact Factor