Gender differences in genetic damage induced by the tobacco-specific nitrosamine NNK and the influence of the Thr241Met polymorphism in the XRCC3 gene

Environ Mol Mutagen. 2005 Jul;46(1):22-9. doi: 10.1002/em.20128.


The rapid increase in adenocarcinoma of the lung and mortality amongst women strongly suggests that gender differences exist in sensitivity to certain tobacco carcinogens. In the current study, we performed the mutagen-sensitivity assay, with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to test the hypothesis that women are more sensitive to the genotoxic effects of NNK than men. Chromosome aberration (CA) frequencies in peripheral blood lymphocytes (PBLs) from 99 patients were evaluated before and after in vitro exposure to NNK. Because the Thr241Met polymorphism in the DNA-repair gene XRCC3 is associated with increased risk of tobacco-related cancers, especially among women, we also tested the hypothesis that individuals who inherit the homozygous variant 241Met allele are more sensitive to the genotoxic effects of NNK. CA frequency was significantly higher 1 hr after NNK treatment in women, compared with men (P = 0.02). When smoking and gender were considered together, a significant interaction was observed. PBLs from female smokers had significantly higher frequencies of NNK-induced CA, compared with female nonsmokers 1 hr after treatment (P = 0.02). We observed no overall effect of the Thr241Met polymorphism on NNK-induced CA in men, women, smokers, or nonsmokers. Overall, our data indicate that women are more sensitive to the genotoxic effects of NNK than men. Because in past years smoking among women has increased, and in view of the close correlation between NNK exposure and adenocarcinoma of the lung, our data provide a plausible explanation for the recent increase in the incidence of this cancer among women.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Cells, Cultured
  • Chromosome Aberrations / drug effects*
  • DNA Damage / genetics
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics*
  • Gene Frequency / drug effects
  • Genotype
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Male
  • Middle Aged
  • Mutagens / isolation & purification
  • Mutagens / toxicity*
  • Nitrosamines / isolation & purification
  • Nitrosamines / toxicity*
  • Polymorphism, Genetic*
  • Sex Factors
  • Smoking / blood
  • Smoking / genetics
  • Tobacco / chemistry*


  • DNA-Binding Proteins
  • Mutagens
  • Nitrosamines
  • X-ray repair cross complementing protein 3
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone