The major objective of this project is to understand the role of human P450s in chemical carcinogenesis and drug therapy. Human P450s are analyzed through use of cDNA expression in a variety of systems including baculovirus, vaccinia virus and lymphoblastoid cells. The latter are commercialized through a cooperative research and development agreement (CRADA) with the Gentest Corporation. A large number of drug and carcinogen substrates have been analyzed for metabolism by different P450 forms. Polymorphisms in P450 gene expression are being determined. An allelic variant was discovered for CYP2C9 that has an Arg to Cys change at residue 144. This change results in a marked difference in warfarin metabolism. The frequency of the minor low activity variant in a population of patients on warfarin therapy is 0.192. A new variant of CYP2D6 was found that has altered catalytic activity toward a selective group of substrates, including debrisoquine. The frequency of this variant is very low. A new genetic polymorphism was found in the gene encoding CYP2A6, a coumarin 7-hydroxylase. Two variant alleles were found that encode catalytically inactive proteins. The frequencies of the variant alleles ranged from 0.025 in African Americans to 0.48 in Japanese subjects.
