CYP3A catalyses schizandrin biotransformation in human, minipig and rat liver microsomes
CYP3A catalyses schizandrin biotransformation in human, minipig and rat liver microsomes
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CYP3A 催化人、小型猪和大鼠肝微粒体中五味子素的生物转化
DOI：
10.3109/00498250903366052
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发表时间：
2010-01-01
期刊：
影响因子：
1.8
通讯作者：
Yang, L.
中科院分区：
文献类型：
--
作者：
Cao, Y. -F.;Zhang, Y. -Y.;Yang, L.
1.五味子醇甲是五味子的主要吸收有效成分，在中药方剂中有着广泛的应用。本研究的目的是描述五味子醇甲的I相代谢产物，并鉴定与之相关的细胞色素P450(CYP)亚型。五味子醇甲与人肝微粒体孵育后，经高效液相色谱分离得到3个代谢物，分别经LC-MS、H-1-核磁共振、C-13-核磁共振鉴定为8(R)-羟基-五味子甲素、2-去甲基-8(R)-羟基-五味子甲素、3-去甲基-8(R)-羟基-五味子甲素。相关分析、化学抑制研究、重组细胞色素P450检测和酶动力学分析相结合的结果表明，五味子醇甲的主要肝脏亚型为CYP3A4。在评估物种差异时，包括了大鼠和小型猪的肝脏微粒体，结果显示物种之间的差异很小。综上所述，细胞色素P3A4在五味子醇甲在人肝微粒体中的生物转化中起着重要作用。在五味子醇药动学研究中，小型猪和大鼠可以作为人的替代模型。了解五味子醇甲的代谢途径可以为了解中药方剂中五味子醇甲的药代动力学行为提供重要信息。
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.