MECHANISM OF NITROSAMINE ALKYLATION OF DNA AND RNA

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The overall aim of the proposed research is to study the mode of action of Beta-oxidized nitrosodialkylamines as carcinogens. The first general objective is to investigate the mechanism by which Beta-oxidized derivatives of nitrosodipropylamine lead to methylation of hepatic DNA following their administration to rats. We will study metabolism and DNA methylation by nitroso-2-hydroxypropylpropylamine (NHPPA) and nitroso-2-oxopropylpropylamine (NOPPA) using rat liver preparations in vitro. In particular, we will determine whether microsomal Alpha-oxidation of the nitrosamines leads to production of a methylating intermediate. We will also investigate the role conjugation of the hydroxyl group of NHPPA plays in its activity as an alkylating agent. The second general objective is to investigate, under well defined in vitro conditions, the acute and chronic effects of 3 other Beta-oxidized derivatives of nitrosodipropylamine: nitrosobis (2-hydroxypropyl) amine (BHP), nitrosobis (2-oxopropyl) amine (BOP), and nitrosobis (2-hydroxypropyl) (2-oxopropyl) amine (HPOP). These nitrosamines are pancreatic carcinogens for the Syrian hamster, and affect both ductular and endocrine, but probably not exocrine portions of the organ. Our use of isolated cell preparations will offer a unique opportunity to study responsive and non-responsive tissue within the same organ. The well-defined culture systems we have developed for the endocrine pancreas of the hamster and rat (non-responsive species) will be utilized to investigate the sequential events, both functional and morphological, following nitrosamine treatment. Our ultimate goal is to determine whether the mechanism of methylation of DNA by BHP and BOP in hamster pancreatic cells is the same as for NHPPA and NOPPA in the rat liver, and whether metabolism of the nitrosamines to the ultimate methylating agent, and subsequent formation and persistence of methylated DNA adducts, is a specific property of nitrosamine-susceptible cells.