人及大鼠肝微粒体中细胞色素P450对雷公藤甲素羟基化作用的表征
Characterization of triptolide hydroxylation by cytochrome P450 in human and rat liver microsomes.
作者信息
Li W, Liu Y, He Y-Q, Zhang J-W, Gao Y, Ge G-B, Liu H-X, Huo H, Liu H-T, Wang L-M, Sun J, Wang Q, Yang L
机构信息
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
出版信息
Xenobiotica. 2008 Dec;38(12):1551-65. doi: 10.1080/00498250802503359.
Triptolide, the primary active component of a traditional Chinese medicine Tripterygium wilfordii Hook F, has a wide range of pharmacological activities. In the present study, the metabolism of triptolide by cytochrome P450s was investigated in human and rat liver microsomes. Triptolide was converted to four metabolites (M-1, M-2, M-3, and M-4) in rat liver microsomes and three (M-2, M-3, and M-4) in human liver microsomes. All the products were identified as mono-hydroxylated triptolides by liquid chromatography-mass spectrometry (LC-MS). The studies with chemical selective inhibitors, complementary DNA-expressed human cytochrome P450s, correlation analysis, and enzyme kinetics were also conducted. The results demonstrate that CYP3A4 and CYP2C19 could be involved in the metabolism of triptolide in human liver, and that CYP3A4 was the primary isoform responsible for its hydroxylation.
雷公藤甲素是中药雷公藤的主要活性成分，具有广泛的药理活性。在本研究中，研究了细胞色素P450在人及大鼠肝微粒体中对雷公藤甲素的代谢作用。雷公藤甲素在大鼠肝微粒体中转化为四种代谢产物（M-1、M-2、M-3和M-4），在人肝微粒体中转化为三种代谢产物（M-2、M-3和M-4）。所有产物均通过液相色谱-质谱联用（LC-MS）鉴定为单羟基化雷公藤甲素。还进行了化学选择性抑制剂、互补DNA表达的人细胞色素P450、相关性分析和酶动力学研究。结果表明，CYP3A4和CYP2C19可能参与人肝中雷公藤甲素的代谢，且CYP3A4是负责其羟基化的主要同工酶。
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