CARCINOGENESIS--HIGHLY REACTIVE NITROSAMINES

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This proposal has as its fundamental and underlying aim a determination of the mechanism by which environmentally prevalent alkyl ethanol nitrosamines, particularly N-nitrosodiethanolamine NDELA, are activated to ultimate carcinogens, and the elucidation of the role that alpha- nitrosamine aldehydes and related compounds may play in this process. Chemical, biochemical, and biological experiments will be used to test the man hypotheses relating to the activation of Beta-nitrosamine ethanols. These hypotheses are: 1) alcohol dehydrogenase mediated oxidation to reactive alpha-nitrosamine aldehydes; 2) Sulfotransferase mediated sulfation followed by the generation of reactive 3-alkyl-1,2,3- oxadiazolinium cations; and 3) chain shortening involving the production of either reactive electrophiles or simple alkyl nitrosamines which are substrates for cytochrome p-450 mediated alpha-hydroxylation. The specific aims are: 1) The determination of the biologically relevant chemistry of alpha-nitrosamine aldehydes, 1,2,3-oxadiazolinium ins, as well as N-nitrosodehydromorpholine and its epoxide in order reveal the likely reactions of these reactive compounds likely to be produced from them modify DNA in vitro. We will continue to elucidate the structure of the major DNA and proteins. 2) The determination of how a-nitrosamine aldehydes and compounds likely to be produced from them modify DNA in vitro. We will continue to elucidate the structure of the major DNA adducts and other DNA modifications produced by alpha-nitrosamine aldehydes, and 3-alkyl-1,2,3-oxadiazolinium ions, and determine the DNA adducts produced from N-nitrosodehydromorpholine and its epoxide. 3) The preparation of specifically deuterated samples of N- nitrosodiethanolamine, methylethanolnitrosamine, and N-nitroso-2- hydroxymorpholine and the determination of the deuterium isotope effects of theses compounds on their enzyme mediated mutagenicity, in vivo DNA alkylation, and in vivo and in vitro DNA single strand breaks, in order to reveal which bioactivation pathways are operative. 4) The determination through model chemical and biochemical experiments of whether a-nitrosamine aldehydes and related alcohols may be activated chain shortened, and/or detoxified through successive one electron oxidations which involve the formation of free radicals. 5) The preparation of 14C-labeled N-nitrosodiethanolamine, and 14C-labeled methylethanolnitrosamine and the determination of their unknown DNA adducts using the chemical models outlined above as markers. The results hold the promise of providing markers for studies in molecular epidemiology and significantly advancing our understanding of chemical carcinogenesis.