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

Abstract

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.

• Authors: Tetsuya Kamataki, Masaki Fujieda, Kazuma Kiyotani, Shunsuke Iwano, Hideo Kunitoh
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 338 Issue 1 Pg. 306-10 (Dec 09 2005) ISSN: 0006-291X [Print] United States
• PMID: 16176798 (Publication Type: Journal Article, Review)

Chemical References

• Mixed Function Oxygenases
• Aryl Hydrocarbon Hydroxylases
• CYP2A6 protein, human
• Cytochrome P-450 CYP2A6

Topics

• Animals
• Aryl Hydrocarbon Hydroxylases (antagonists & inhibitors, genetics)
• Cytochrome P-450 CYP2A6
• Humans
• Lung Neoplasms (drug therapy, enzymology, epidemiology, genetics)
• Mice
• Mice, Inbred A
• Mixed Function Oxygenases (antagonists & inhibitors, genetics)
• Polymorphism, Genetic
• Risk Factors
• Smoking (adverse effects, genetics)