DNA adducts of environmental carcinogens have the potential of leading to tumor initiation through mutation. Genetic polymorphisms in the enzymes activating carcinogens to DNA binding forms could contribute to individual variations in cancer risk. The roles of such polymorphisms in formation of DNA adducts of the food carcinogen 2-amino-3- methylimidazo[4,5-f]quinoline (IQ) were studied by 32P-postlabeling in mouse strains congenic for inducible vs noninducible P450 1A and for slow vs rapid N-acetylation. In Ah-nonresponsive mice, rapid acetylators formed threefold more IQ-DNA adducts in colon than slow acetylators (P is less than 0.05), consistent with greater risk of colon cancer among human rapid acetylators. Adduct levels in bladder were significantly elevated only following beta-naphthoflavone pretreatment of Ah- responsive, rapid acetylators. The results suggest that formation of DNA adducts of IQ are potentially relevant to human cancer risk and are modulated in both colon and bladder, in organ-specific ways, by both Ah and NAT polymorphisms. Another important issue, with regard to DNA adducts, is the nature of events related to adduct formation and repair at very low doses. We have studied low dose-DNA adduct phenomena in rats given the environmental nitrosamine N-nitrosodimethylamine (NDMA) in drinking water, using a highly sensitive competitive repair assay for a major promutagenic adduct formed from NDMA, O6-methylguanine (MeG). Levels of this adduct were linear over the dose range 0-0.5 ppm. There was then a break in the curve with a reduction in slope; dose-response from 0.5 - 2.6 ppm was again linear. This suggested that very low exposure yielded disproportionately high amounts of MeG. Disappearance of adducts after acute treatment or cessation of chronic treatment was biphasic, with a rapid (t 1/2 = 1/5 hrs, 70% of adducts) followed by a slow loss (t 1/2 = 24 hrs). The mechanistic differences in these repair phases are of potential importance and are under investigation.
