CYP2C9基因多态性对人肝微粒体中丙戊酸肝毒性代谢产物形成的影响。

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes.

作者信息

Ho P C, Abbott F S, Zanger U M, Chang T K H

机构信息

1Faculty of Pharmaceutical Sciences, The University of British Columbia, British Columbia, Canada.

出版信息

Pharmacogenomics J. 2003;3(6):335-42. doi: 10.1038/sj.tpj.6500210.

DOI:10.1038/sj.tpj.6500210

PMID:14597963

Abstract

The present study investigated the effect of cytochrome P450 2C9 (CYP2C9) genetic polymorphism on the biotransformation of valproic acid (VPA) to its hepatotoxic metabolite, 4-ene-VPA, and compared that to the formation of the inactive 4-OH-VPA and 5-OH-VPA. cDNA-expressed CYP2C9()2 and CYP2C9()3 variants were less efficient than the CYP2C9()1 wild type in catalyzing the formation of these metabolites, as assessed by the ratio of Vmax and apparent Km (in vitro intrinsic clearance). The reduced efficiency by CYP2C9()2 was due to a reduced Vmax, whereas, in the case of CYP2C9()3, it was the result of increased apparent Km. The formation rates of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA in human liver microsomes were reduced by 29, 28, and 31%, respectively, in samples with one mutated CYP2C9 allele, and by 61, 73, and 58%, respectively, in samples with two mutated CYP2C9 alleles. Overall, the homozygote and heterozygote CYP2C9()2 and CYP2C9(*)3 genotypes may compromise hepatic VPA biotransformation.

摘要

本研究调查了细胞色素P450 2C9（CYP2C9）基因多态性对丙戊酸（VPA）向其肝毒性代谢物4-烯-VPA生物转化的影响，并将其与无活性的4-羟基-VPA和5-羟基-VPA的形成进行比较。通过Vmax与表观Km的比值（体外内在清除率）评估，cDNA表达的CYP2C9（）2和CYP2C9（）3变体在催化这些代谢物形成方面比CYP2C9（）1野生型效率更低。CYP2C9（）2效率降低是由于Vmax降低，而对于CYP2C9（）3，是表观Km增加的结果。在具有一个突变CYP2C9等位基因的样本中，人肝微粒体中4-烯-VPA、4-羟基-VPA和5-羟基-VPA的形成率分别降低了29%、28%和31%，在具有两个突变CYP2C9等位基因的样本中分别降低了61%、73%和58%。总体而言，CYP2C9（）2和CYP2C9（*）3基因型的纯合子和杂合子可能会损害肝脏VPA生物转化。