ENDOGENOUS ADDUCTS AND ENVIRONMENTAL CARCINOGENS

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Recent improvements in analytical technology have led to the discovery of endogenous adducts in DNA of animals and humans. The occurrence of these endogenous adducts raises questions as to the mechanism of their formation and their role in the development of carcinogenesis. This proposal will investigate the role of lipid peroxidation in the formation of endogenous N2, 3-ethenoguanine (epsilonG), a DNA adduct formed by many carcinogens. The specific aim of this project will address lipid peroxidation as the possible source of endogenous epsilonG in rat. The role of lipid peroxidation in the formation of epsilonG will initially be investigated in rat liver nuclei and in hepatocytes in which lipid peroxidation is induced by iron- derived Fenton-type reactions. These investigations will continue in whole animal studies in which lipid peroxidation will be induced by the depletion of glutathione by L-buthionine-S, R-sulfoximine (BSO), a specific inhibitor of glutathione synthesis. Additionally, the formation and repair of endogenously formed epsilonG will be compared and contrasted to its formation resulting from alkylation of DNA by vinyl chloride. The formation of endogenous epsilonG will be examined in animals exposed to [13C2] vinyl chloride, a carcinogen that forms epsilonG through direct alkylation of DNA by its metabolites. The formation of epsilonG from endogenous sources and directlyfrom vinyl chloride exposure will be compared and contrasted. These studies will provide information about the formation of DNA adducts from endogenous sources that could increase understanding of the development of cancer and could influence carcinogen risk assessment.