人细胞色素P450 2C91、2C93和2C9*13的催化活性。

Catalytic activities of human cytochrome P450 2C91, 2C93 and 2C9*13.

作者信息

Guo Y, Wang Y, Si D, Fawcett P J, Zhong D, Zhou H

机构信息

College of Life Science, Jilin University, Changchun, China.

出版信息

Xenobiotica. 2005 Sep;35(9):853-61. doi: 10.1080/00498250500256367.

DOI:10.1080/00498250500256367

PMID:16308280

Abstract

Cytochrome P450 2C9 (CYP2C9) is a geneticly polymorphic enzyme responsible for the metabolism of some clinically important drugs. CYP2C913 is an allele identified in a Chinese poor metabolizer of lornoxicam which has a Leu90Pro amino acid substitution. This paper reports on a study aimed at comparing the catalytic properties of CYP2C913 with those of the wild-type CYP2C91 and mutant CYP2C93 (Ile359Leu) in the COS-7 expression system using various substrates. CYP2C93 and 13 produced far lower luminescence than CYP2C91 in luciferin H metabolism. CYP2C913 exhibited an 11-fold increase in Km but no change in Vmax with tolbutamide as the substrate, a five-fold increase in Km and an 88.8% reduction in Vmax with diclofenac. These data indicate that CYP2C913 exhibits reduced metabolic activity toward all studied CYP2C9 substrates. The magnitude of the CYP2C913-associated decrease in intrinsic clearance (Vmax/Km) is greater than that associated with CYP2C9*3.

摘要

细胞色素P450 2C9（CYP2C9）是一种具有遗传多态性的酶，负责某些临床重要药物的代谢。CYP2C913是在一名氯诺昔康代谢不良的中国患者中鉴定出的一个等位基因，该等位基因发生了Leu90Pro氨基酸替换。本文报道了一项研究，旨在使用各种底物在COS-7表达系统中比较CYP2C913与野生型CYP2C91和突变型CYP2C93（Ile359Leu）的催化特性。在荧光素H代谢中，CYP2C93和13产生的发光远低于CYP2C91。以甲苯磺丁脲为底物时，CYP2C913的Km增加了11倍，但Vmax没有变化；以双氯芬酸为底物时，Km增加了5倍，Vmax降低了88.8%。这些数据表明，CYP2C913对所有研究的CYP2C9底物的代谢活性均降低。与CYP2C913相关的内在清除率（Vmax/Km）降低幅度大于与CYP2C9*3相关的降低幅度。