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

Biochem Biophys Res Commun. 2005 Dec 9;338(1):306-10. doi: 10.1016/j.bbrc.2005.08.268. Epub 2005 Sep 15.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • 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*
  • Polymorphism, Genetic*
  • Risk Factors
  • Smoking / adverse effects
  • Smoking / genetics*

Substances

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