Two linked mutations in transcriptional regulatory elements of theCYP3A5gene constitute the major genetic determinant of polymorphic activity in humans
作者:
Aimée Paulussen,
Karel Lavrijsen,
Hilde Bohets,
Jan Hendrickx,
Peter Verhasselt,
Walter Luyten,
Frank Konings,
Martin Armstrong,
期刊:
Pharmacogenetics
(OVID Available online 2000)
卷期:
Volume 10,
issue 5
页码: 415-424
ISSN:0960-314X
年代: 2000
出版商: OVID
关键词: CYP3A5;gene;polymorphism;expression;metabolism
数据来源: OVID
摘要:
Cytochrome P450 3A subfamily members (CYP3A) are the most abundant liver cytochrome P450 forms, responsible for the biotransformation of over 50% of all drugs. The expression and activity of isoforms CYP3A4 and CYP3A5 show wide inter-individual variation, influencing both drug response and disease susceptibility. The molecular basis for this variation has never been defined. In this study, we used midazolam to characterize CYP3A5 phenotype in a panel of liver samples. A clear bimodality in metabolism was observed. Analysis of the 5′ flanking region of theCYP3A5gene identified two linked polymorphisms, T−369G and A−45G, located in transcriptional regulatory elements which are associated with increased expression and activity of the gene. A polymerase chain reaction based detection assay is described facilitating future studies into both the metabolic consequences of this variation and disease association studies relating to CYP3A5.
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