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 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.
Paulussen
A
A
Department of Pharmacogenomics, Janssen Research Foundation, Janssen Pharmaceutica, Beerse, Belgium.
Lavrijsen
K
K
Bohets
H
H
Hendrickx
J
J
Verhasselt
P
P
Luyten
W
W
Konings
F
F
Armstrong
M
M
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
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