ENDOGENOUS ADDUCTS AND ENVIRONMENTAL CARCINOGENS

最近分析技术的改进导致了这一发现 内源性加合物在动物和人类的DNA。 的 这些内源性加合物的出现引起了关于 其形成机制及其在发展中的作用 致癌作用 这项提案将探讨脂质的作用 内源性N2，3-乙烯基鸟嘌呤形成中的过氧化作用 （ε G），由许多致癌物形成的DNA加合物。 具体 本项目的目的是将脂质过氧化作为可能的来源 内源性ε G的表达。 脂质过氧化在肝硬化中的作用 将首先在大鼠肝细胞核中研究ε G的形成 在铁诱导脂质过氧化的肝细胞中， Fenton型反应。 这些调查将在 整个动物研究，其中脂质过氧化将由 L-丁硫氨酸-S，R-亚砜亚胺（BSO），a 谷胱甘肽合成的特异性抑制剂。 此外，编队 并比较内源性形成的epsilonG的修复， 与乙烯基对DNA进行烷基化而形成的 氯化 内源性ε G的形成将在 接触[13C2]氯乙烯的动物，氯乙烯是一种致癌物质， epsilonG通过其代谢产物直接烷基化DNA。 的 从内源性来源和直接从乙烯基形成ε G 将比较和对比氯化物暴露。 这些研究将 提供有关DNA加合物形成的信息， 内源性来源，可以增加对 癌症的发展，并可能影响致癌物的风险评估。

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.