Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans

Cytochrome P450 3A subfamily members (CYP3A) are the most abundant liver cy tochrome P450 forms, responsible for the biotransformation of over 50% of a ll drugs. The expression and activity of isoforms CYP3A4 and CYP3A5 show wi de inter-individual variation, influencing both drug response and disease s usceptibility. The molecular basis for this variation has never been define d. In this study, we used midazolam to characterize CYP3A5 phenotype in a p anel of liver samples. A clear bimodality in metabolism was observed. Analy sis of the 5' flanking region of the CYP3A5 gene identified two linked poly morphisms, T(-369)G and A(-45)G, located in transcriptional regulatory elem ents which are associated with increased expression and activity of the gen e. A polymerase chain reaction based detection assay is described facilitat ing future studies into both the metabolic consequences of this variation a nd disease association studies relating to CYP3A5. Pharmacogenetics 10:415- 424 (C) 2000 Lippincott Williams & Wilkins.