This project has recently been focused on genetic differences that determine the consequences of exposure to environmental carcinogens, in both animal models and human populations. Work has been completed on the formation of DNA adducts by the arylamine food mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), in C57BL/6 mice congenic for nonresponsiveness at the Ah receptor(Ahr) locus. In the absence of any enzyme induction, the profile of IQ/DNA adducts in lung was markedly different in the two strains, and livers of Ahr- responsive mice formed 18-fold more IQ/DNA adducts than those of nonresponsive mice. These results indicate heretofore unsuspected qualitative and quantitative contributions of the Ah receptor to DNA adduct formation and hence possibly to tumorigenesis. This receptor may be polymorphic in humans. Analysis is nearing completion on the role of genetic polymorphisms in the cytochrome (CYP) 2E1 gene in susceptibility to nasopharyngeal carcinoma in Chinese. Results thus far are striking. Among nonsmokers, the rarer allele was associated in homozygotes with a 10-fold increase in risk. Since this allele may increase gene expression, the results are consistent with increased rate of activation of dietary or environmental nitrosamines in nasal tissue. In contrast, among smokers, risk of nasopharyngeal carcinoma was overall less, and was greatest in those individuals homozygous for the commoner, wild-type allele. Among these individuals, an apparent dose-dependent increase in risk due to smoking was observed. These results suggest marked differences in the contribution of particular genotypes to risk, depending on the exposure situation. Analysis of dietary and other exposure factors is in progress.
