Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk
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- 作者：Tetsuya Kamataki ; Masaki Fujieda ; Kazuma Kiyotani ; Shunsuke Iwano ; Hideo Kunitoh
- 关键词：P450 2A6 ; CYP2A6*4C ; Single nucleotide polymorphism(s) ; NNK ; Smokers ; Smoking ; Case-control study
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2005
- 出版时间：9 December 2005
- 年：2005
- 卷：338
- 期：1
- 页码：306-310
- 全文大小：129 K
文摘
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.