Genetic polymorphism of CYP2A6 in relation to cancer

To clarify the roles of human cytochrome P450 (P450 or CYP) 2A6 and 2E1 on the metabolic activation of N-nitrosamines, we established genetically engi neered Salmonella typhimurium strains harboring human CYP2A6 or CYP2E1 toge ther with NADPH-P450 reductase (OR). The 5'-terminus of CYP cDNA was modifi ed to achieve a high-level expression in S. typhimurium. Modified CYP2A6 or CYP2E1 cDNA and native OR cDNA were introduced into a pCW vector. S. typhi murium YG7108 cells were transformed with this vector. The mutagen producin g ability of these enzymes for some N-nitrosamines were evaluated using the established S. typhimurium cells. We found that the substrate specificity of CYP2A6 and CYP2E1 was different among mutagens. CYP2A6 was responsible f or the metabolic activation of N-nitrosamines possessing relatively long al kyl chains, whereas CYP2E1 was responsible for the metabolic activation of N-nitrosamines with relatively short alkyl chains. It is likely that CYP2A6 gene polymorphism is responsible for the interindividual variability on th e cancer susceptibility. We found the whole deletion of CYP2A6 gene as a ty pe of genetic polymorphism in Japanese. Thus, we developed a gene diagnosis method to detect the variant. We evaluated the relationship between the CY P2A6 gene whole deletion and the susceptibility to the lung cancer. The fre quency of CYP2A6 gene whole deletion was significantly lower in the lung ca ncer patients than that of healthy volunteers. (C) 1999 Elsevier Science B. V. All rights reserved.