Contribution of genetic and nutritional factors to DNA damage in heavy smokers

Prior epidemiological evidence suggests that genes controlling themetabolism of carcinogens and antioxidant/nutritional status are associatedwith lung cancer risk, possibly through their ability to modulate DNAdamage by carcinogens. We performed a cross-sectional analysis of 159 heavysmokers from a cohort of subjects enrolled in a smoking cessation program.A total of 159 blood samples were analyzed to determine the relativecontributions of genetic polymorphisms [CYP1A1 MspI and exon 7 andglutathione S-transferase M1 (GSTM1)] and plasma micronutrients topolycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage insmokers was affected by genetic polymorphisms and nutritional status.Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher(2-fold, P < or = 0.03) levels of DNA damage than those without. Inparallel models, PAH-DNA adducts were inversely associated with plasmalevels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P= 0.09), and alpha- tocopherol (beta = -0.28, P = 0.21) in 159 subjects.The association between smoking-adjusted plasma beta-carotene levels andDNA damage was only significant in those subjects lacking the GSTM1detoxification gene (beta = -0.30, P = 0.05, n = 75). There was astatistical interaction between beta-carotene and alpha-tocopherol; whenbeta- carotene was low, alpha-tocopherol had a significant protectiveeffect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene washigh (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantlycorrelated with beta-carotene (r = 0.36, P = 0.0005) and less strongly withretinol (r = 0.20, P = 0.0005). These results suggest that severalmicronutrients may act in concert to protect against DNA damage andhighlight the importance of assessing overall antioxidant status. Inconclusion, a subset of smokers may be at increased risk of DNA damage andpossibly lung cancer due to the combined effect of low plasmamicronutrients and genetic susceptibility factors. The use of biologicalmarkers to assess efficacy of interventions and to study mechanisms ofmicronutrients is timely given the current debate regarding the use ofchemopreventive agents in high risk populations.