Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans
Paulussen, A × Lavrijsen, K Bohets, H Hendrickx, J Verhasselt, P Luyten, Walter Konings, F Armstrong, M #
Chapman & Hall
Pharmacogenetics vol:10 issue:5 pages:415-424
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 the CYP3A5 gene identified two linked polymorphisms, T(-369)G and A(-45)G, 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. Pharmacogenetics 10:415-424 (C) 2000 Lippincott Williams & Wilkins.