title: Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans.
abstract: 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-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.
authors.affiliation: Department of Pharmacogenomics, Janssen Research Foundation, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Paulussen
authors.forename: K
authors.initials: K
authors.lastname: Lavrijsen
authors.forename: H
authors.initials: H
authors.lastname: Bohets
authors.forename: J
authors.initials: J
authors.lastname: Hendrickx
authors.forename: P
authors.initials: P
authors.lastname: Verhasselt
authors.forename: W
authors.initials: W
authors.lastname: Luyten
authors.forename: F
authors.initials: F
authors.lastname: Konings
authors.forename: M
authors.initials: M
authors.lastname: Armstrong
mesh_terms: D020121:5' Untranslated Regions / Q000032:analysis; D000483:Alleles; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D005787:Gene Frequency; D008040:Genetic Linkage; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D020121:5' Untranslated Regions; D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam