CYP3A catalyses schizandrin biotransformation in human, minipig and rat liver microsomes

被引：42
作者：
Cao, Y. -F. [1 ]
Zhang, Y. -Y. [2 ,3 ]
Li, J. [1 ]
Ge, G. -B. [2 ]
Hu, D. [1 ]
Liu, H. -X. [2 ,3 ]
Huang, T. [1 ]
Wang, Y. -C. [1 ]
Fang, Z. -Z. [2 ,3 ]
Sun, D. -X. [1 ]
Huo, H. [2 ]
Yin, J. [1 ]
Yang, L. [2 ]
机构：
[1] Shenyang Pharmaceut Univ, Sch Tradit Chinese Med, Shenyang 110016, Peoples R China
[2] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
[3] Chinese Acad Sci, Grad Sch, Beijing, Peoples R China
来源：
XENOBIOTICA | 2010年 / 40卷 / 01期
基金：
中国国家自然科学基金;
关键词：
Schizandrin; cytochrome P450; microsomes; metabolism; Fructus schisandrae; HUMAN CYTOCHROME-P450 ENZYMES; MEDROXYPROGESTERONE ACETATE; IN-VITRO; METABOLISM; INHIBITION; EXTRACT; FRUIT; ISOFORMS; PLASMA; VIVO;
D O I：
10.3109/00498250903366052
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
1. Schizandrin is recognized as the major absorbed effective constituent of Fructus schisandrae, which is extensively applied in Chinese medicinal formula. The present study aimed to profile the phase I metabolites of schizandrin and identify the cytochrome P450 (CYP) isoforms involved. 2. After schizandrin was incubated with human liver microsomes, three metabolites were isolated by high-performance liquid chromatography (HPLC) and their structures were identified to be 8(R)hydroxyl-schizandrin, 2-demethyl-8(R)-hydroxyl-schizandrin, 3-demethyl-8(R)-hydroxyl-schizandrin,by liquid chromatography-mass spectrometry (LC-MS), H-1-nuclear magnetic resonance (NMR), and C-13-NMR, respectively. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs, and enzyme kinetics indicated that CYP3A4 was the main hepatic isoform that cleared schizandrin. Rat and minipig liver microsomes were included when evaluating species differences, and the results showed little difference among the species. 3. In conclusion, CYP3A4 plays a major role in the biotransformation of schizandrin in human liver microsomes. Minipig and rat could be surrogate models for man in schizandrin pharmacokinetic studies. Better knowledge of schizandrin's metabolic pathway could provide the vital information for understanding the pharmacokinetic behaviours of schizandrin contained in Chinese medicinal formula.
引用
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页码：38 / 47
页数：10
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