Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins P B, Daly A, Wrighton S A, Hall S D, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski M S, Schuetz E
Department of Molecular and Cell Biology, University of Maryland at Baltimore, Baltimore, Maryland, USA.
Nat Genet. 2001 Apr;27(4):383-91. doi: 10.1038/86882.
Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A51 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A53 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.
参与药物代谢的细胞色素P450 3A（CYP3A）酶的变异会影响循环类固醇水平以及对所有氧化代谢药物中半数药物的反应。CYP3A活性是CYP3A基因家族的总活性，其中包括CYP3A5，在少数欧洲裔美国人和欧洲人（以下统称为“白种人”）中，CYP3A5呈多态性高表达。只有拥有至少一个CYP3A51等位基因的人才会大量表达CYP3A5。我们的研究结果表明，CYP3A53和CYP3A5*6中的单核苷酸多态性（SNP）会导致选择性剪接和蛋白质截短，从而使一些人的组织中缺乏CYP3A5。与白种人（33%）相比，非裔美国人肝脏中CYP3A5的表达更为频繁（60%）。由于在多态性表达CYP3A5的人群中，CYP3A5至少占肝脏总CYP3A含量的50%，因此CYP3A5可能是导致个体间和种族间CYP3A依赖性药物清除以及对多种药物反应存在差异的最重要遗传因素。
