The investigations that are carried out as part of this project relate to gene structure, and alteration in this structure, as contributing factors in sensitivity to causation of cancers by environmental carcinogens. During this year, emphasis has been placed on two important carcinogen classes, nitrosamines, such as N-nitrosodimethylamine (NDMA) that are metabolized by cytochrome P450 (cyp) 2E1, and aryl amine food mutagens, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), which is sequentially activated by CYP1A2 and N-acetyltransferase (NAT). Polymorphisms in all of these genes have been implicated in human cancer risk. A study has been completed of formation of the promutagen DNA adduct, O6-methylguanine (O6-meG) in rat liver and white blood cells by low doses of NDMA, given acutely or in drinking water. In the chronic study, rate of adduct formation was greater at doses of 0.4 ppm and below, than at higher doses. Measurement of the time course of repair after single acute doses confirmed a biphasic repair rate, which may indicate damage in different cell populations. Comparison of adduct levels in DNA of blood cells and liver within this extensive data set confirm the usefulness of measurement of adducts in blood cells, which are used in biomarker studies, as an indicator of adducts in internal organs. A new study regarding CYP2E1 and its relation to human cancer risk has been started in collaboration with the Environmental Epidemology Branch and involves determination of polymorphisms in this gene in Chinese nasopharyngeal cancer patients. A correlating effort is being undertaken with the patas monkey model to establish an experimental model for study of the meaning of CYP2E1 polymorphisms. With regard to carcinogenesis by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a study is nearing completion of the roles of polymorphisms in metabolism of this compound, using congenic mouse strains polymorphic for inducibility of CYP1A2 via the Ah receptor and for fast vs slow NAT. Adducts on DNA were quantified by 32P-postlabeling. In liver, Ah responsiveness strongly potentiated adduct formation. In lung, the qualitative profile of adducts was also affected by Ah genotype, regardless of enzyme induction. These findings have potential meaning in the context of human polymorphisms in the Ah receptor.
