Genetic Polymorphism of CYP2A6 and Tobacco-Related Cancer Risk: From the Establishment of Genetically Engineered Salmonella to Large Scale Epidemiology

Abstract

Most mutagens/carcinogens are metabolically activated by enzymes such as cytochrome P450 to exert their mutagenicity or carcinogenicity. Since the catalytic properties of cytochrome P450 vary among animal species, it was necessary to establish a mutation-detection system carrying human cytochrome P450 to estimate if the chemicals are mutagenic in humans. For this purpose, we introduced genes for human cytochrome P450 together with NADPH-cytochrome P450 reductase to establish humanized Salmonella typhimurium. Using the genetically engineered Salmonella typhimurium, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke. Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype towards (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazoline-4-one hydrochloride (SM-12502), we discovered a novel mutant allele (CYP2A6*4C) lacking the whole CYP2A6 gene. Taking these results into account, we hypothesized that the subjects carrying the CYP2A6*4C allele had lower risk to tobacco-related lung cancer. In accordance with our hypothesis, our large scale epidemiological studies clearly indicated that smokers homozygous for the CYP2A6*4C allele showed much smaller odds ratios towards cancer risk. Other mutant alleles reducing the CYP2A6 activity besides the CYP2A6*4C allele also reduced the risk for lung cancer in smokers, particularly squamous cell carcinoma and small cell carcinoma frequently seen in smokers. 8-Methoxypsoralen, an inhibitor of CYP2A6, efficiently prevented the occurrence of adenoma caused by NNK in A/J mice.