Cao Y-F, Zhang Y-Y, Li J, Ge G-B, Hu D, Liu H-X, Huang T, Wang Y-C, Fang Z-Z, Sun D-X, Huo H, Yin J, Yang L
School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China.
Xenobiotica. 2010 Jan;40(1):38-47. doi: 10.3109/00498250903366052.
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. 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), (1)H-nuclear magnetic resonance (NMR), and (13)C-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. 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.
五味子醇甲被认为是五味子的主要吸收有效成分，广泛应用于中药配方中。本研究旨在剖析五味子醇甲的I相代谢产物，并确定参与其中的细胞色素P450（CYP）同工酶。将五味子醇甲与人肝微粒体孵育后，通过高效液相色谱（HPLC）分离出三种代谢产物，并分别通过液相色谱-质谱联用（LC-MS）、氢核磁共振（1H-NMR）和碳核磁共振（13C-NMR）鉴定其结构为8（R）-羟基五味子醇甲、2-去甲基-8（R）-羟基五味子醇甲、3-去甲基-8（R）-羟基五味子醇甲。相关性分析、化学抑制研究、重组CYP检测和酶动力学相结合表明，CYP3A4是清除五味子醇甲的主要肝同工酶。在评估种属差异时纳入了大鼠和小型猪肝微粒体，结果显示种属间差异不大。总之，CYP3A4在人肝微粒体中五味子醇甲的生物转化中起主要作用。小型猪和大鼠可作为五味子醇甲药代动力学研究中的人类替代模型。更好地了解五味子醇甲的代谢途径可为理解中药配方中五味子醇甲的药代动力学行为提供重要信息。
