CONTRIBUTION OF GENETIC AND NUTRITIONAL FACTORS TO DNA-DAMAGE IN HEAVY SMOKERS

Prior epidemiological evidence suggests that genes controlling the met abolism of carcinogens and antioxidant/nutritional status are associat ed with lung cancer risk, possibly through their ability to modulate D NA damage by carcinogens. We performed a cross-sectional analysis of 1 59 heavy smokers from a cohort of subjects enrolled in a smoking cessa tion program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and e xon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrie nts to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DN A damage in smokers was affected by genetic polymorphisms and nutritio nal status. Smokers with the CYP1A1 exon 7 valine polymorphism had sig nificantly higher (2-fold, P less than or equal to 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were i nversely associated with plasma levels of retinol (beta = -0.93, P = 0 .01), beta-carotene (P = -0.18, P = 0.09), and a-tocopherol (beta = -0 .28, P = 0.21) in 159 subjects. The association between smoking-adjust ed plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-caro tene and alpha-tocopherol; when beta-carotene was low, alpha-tocophero l had a significant protective effect (beta = -0.78, P = 0.04) on addu cts, but not when beta-carotene was high (P = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.000 5). These results suggest that several micronutrients may act in conce rt to protect against DNA damage and highlight the importance of asses sing overall antioxidant status. In conclusion, a subset of smokers ma y be at increased risk of DNA damage and possibly lung cancer due to t he combined effect of low plasma micronutrients and genetic susceptibi lity factors. The use of biological markers to assess efficacy of inte rventions and to study mechanisms of micronutrients is timely given th e current debate regarding the use of chemopreventive agents in high r isk populations.