CARCINOGENESIS--HIGHLY REACTIVE NITROSAMINES

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DESCRIPTION: This proposal seeks to understand the mechanism of the carcinogenesis of nitrosodiethanolamine (NDELA) and other beta-oxidized nitrosamines. Secondary alkanolamines are widely distributed and their nitrosoamine derivatives are documented in lubricants and metal-working fluids. NDELA is a known carcinogen but unlike most nitrosodialkylamines, it is not mutagenic in the Ames test in the presence of microsomal enzymes. Thus, beta-oxidized dialkylnitrosamines appear to have a mechanism of activation that is in some way novel. Basically, hypotheses about three modes of activation are entertained with some contribution by each of the three being an additional possibility. a) It is possible that these compounds do undergo the "normal" alpha-oxidation to reactive alpha-hydroxynitrosamines by some as yet unrecognized enzyme activity, but that this was not detected in earlier studies. b) It is possible that these compounds are activated by beta-oxidation to aldehydes that subsequently cyclize and undergo further metabolic activation. c) It is possible that these molecules are activated through sulfation at the beta-position and subsequently form reactive oxadiazolinium ion intermediates. The work proposed involves: synthesis of additional DNA base adducts that could be formed from proposed intermediates; analysis of reaction chemistry and products of model reactions that could account for some known adducts and or reactions; establishing whether NDELA is in fact a substrate for some microsomal enzymes, analysis of isotope effects on 32P-postlabeling profiles to determine the dependence of adducts upon the site of oxidation; and analysis of formation in vivo of an adduct isolated from in vitro reactions that is characteristic of one of the pathways above.