Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver

The human cytochrome P450, CYP2B6, is involved in the metabolism of several therapeutically important drugs and environmental or abused toxicants, In this study, we present the first systematic Investigation of genetic polymo rphism in the CYP2B6 gene on chromosome 19, A specific direct: sequencing s trategy was developed based on CYP2B6 and CYP2B7 genomic sequence informati on and DNA from 35 subjects was completely analysed for mutations throughou t all nine exons and their exon-intron boundaries, A total of nine novel po int mutations were identified, of which five result in amino acid substitut ions in exon 1 (664T, Arg(22)Cys), exon 4 (G516T, Gln(172)His), exon 5 (C77 7A, Ser(259)Arg and A785G, Lys(262)Arg) and exon 9 (C1459T, Arg(487)Cys) an d four are silent mutations (C78T, G216C, G714A and C732T), Polymerase chai n reaction-restriction fragment length polymorphism tests were developed to detect each of the five nonsynonymous mutations in genomic DNA, By screeni ng a population of 215 subjects the C64T, G516T, C777A, A785G and C1459T mu tations were found at frequencies of 5.3%, 28.6%, 0.5%, 32.6% and 14.0%, re spectively, Haplotype analysis revealed six different mutant alleles termed CYP2B6*2 (C64T), *3 (C777A), *4 (A785G), *5 (C1459T), *6 (G516T and A785G) and *7 (G516T, A785G and C1459T). By analysing a large number of human liv er samples, significantly reduced CYP2B6 protein expression and S-mephenyto in N-demethylase activity were found in carriers of the C1459T (R487C) muta tion (alleles *5 and *7), These data demonstrate that the extensive interin dividual variability of CYP2B6 expression and function is not only due to r egulatory phenomena, but also caused by a common genetic polymorphism, Phar macogenetics 11:399-415 (C) 2001 Lippincott Williams & Wilkins.