Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression
Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression
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DOI：
10.1038/86882
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发表时间：
2001-04-01
期刊：
影响因子：
30.8
通讯作者：
Schuetz, E
中科院分区：
文献类型：
--
作者：
Kuehl, P;Zhang, J;Schuetz, E
在药物代谢中起作用的CYP3A酶的变化影响循环类固醇水平和对所有氧化代谢药物的一半的反应。CYP3A活性是CYP3A基因家族的总活性，包括CYP3A5，其在少数欧洲血统的美国人和欧洲人中以高水平多态性表达，此后统称为“高加索人”。只有至少有一个CYP3A5*1等位基因的人表达大量的CYP3A5。我们的研究结果表明，CYP3A5*3和CYP3A5*6中的单核苷酸多态性（SNP）导致选择性剪接和蛋白质截短，导致一些人的组织中缺乏CYP3A5。CYP3A5在非裔美国人（60%）的肝脏中的表达频率高于白人（33%）。由于CYP3A5在多态性表达CYP3A5的人群中至少占肝脏CYP3A总含量的50%，因此CYP3A5可能是CYP3A依赖性药物清除率和对许多药物反应的个体间和种族间差异的最重要遗传因素。
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 thereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 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.