ENDOGENOUS NITROSATION CHEMISTRY IN CARCINOGENESIS

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The goal of this research is to provide knowledge and practical strategies for the significant reduction of carcinogenesis which may arise from endogenous nitrosation processes which can generate electrophilic species capable of modifying DNA and causing mutations. The principle hypothesis of this proposal is that significant progress toward this goal can be achieved 1) by showing through logical experimentation what can be made; 2) by elucidating the chemistry of processes which may catalyze or otherwise facilitate, as well as block, the N-nitrosation of available substrates and the production of electrophiles, and 3) by providing available markers, such as DNA adducts or other products, of genotoxicity which could be used in epidemiological studies to make connections between endogenous nitrosation chemistry and cancer. Our focus is directed at revealing the role that nitrosation of compounds containing C-N double bonds may play in the generation of cell damaging electrophiles, and how this process, as well as the nitrosation of other substrates, may occur through the reaction of NO with radical cations produced by oxidation processes such as those which occur at inflammation sites. Model substrates and drugs containing the oxazoline, imidazoline, and benzodiazepine rings will be nitrosated under endogenous conditions and the nature of the electrophiles arising from these transformations identified and the nature of their DNA adducts determined when appropriate. Both acidic nitrosation and NO + O2 Dietary aldehydes and ketones, including sugars, will be examined for their ability to catalyze the nitrosative conversion of primary amines, including amino acids, to diazonium ions, alpha-acyloxynitrosamines, or alpha-hydroxynitrosamines. The ability of NO mediated damage to occur by its reaction with radical cations produced by other oxidative processes will be probed. Computational methods will be employed to reveal reaction paths of intermediates and lead to better predictions of the types of compounds which pose a carcinogenic threat through their endogenous nitrosation.