Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk

• Published in: Biochemical and biophysical research communications Vol. 338; no. 1; pp. 306 - 310
• Main Authors: Kamataki, Tetsuya, Fujieda, Masaki, Kiyotani, Kazuma, Iwano, Shunsuke, Kunitoh, Hideo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.12.2005
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - genetics; Case-control study; CYP2A6 4C; Cytochrome P-450 CYP2A6; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - epidemiology; Lung Neoplasms - genetics; Mice; Mice, Inbred A; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - genetics; NNK; P450 2A6; Polymorphism, Genetic; Risk Factors; Salmonella typhimurium; Single nucleotide polymorphism(s); Smokers; Smoking; Smoking - adverse effects; Smoking - genetics; P450 2A6; CYP2A6 4C; Smokers; Single nucleotide polymorphism(s); Case-control study; NNK; Smoking
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.08.268

Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype toward SM-12502, we discovered a novel mutant allele ( CYP2A6* 4C) lacking the whole CYP2A6 gene. Using genetically engineered Salmonella typhimurium expressing a human CYP, 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. Taking these results into consideration, we hypothesized that the subjects carrying the CYP2A6* 4C allele had lower risk of tobacco-related lung cancer. In accordance with our hypothesis, our epidemiological studies indicated that smokers homozygous for the CYP2A6* 4C allele showed much lower odds ratios toward cancer risk. Other mutant alleles reducing the CYP2A6 activity, besides CYP2A6* 4C, also reduced the risk of lung cancer in smokers, particularly of squamous-cell carcinoma and small-cell carcinoma, both smoking-related cancers. 8-Methoxypsoralen, an inhibitor of CYP2A6, efficiently prevented the occurrence of adenoma caused by NNK in A/J mice.