PANCREAS AND LIVER CARCINOGEN METABOLISM IN TWO SPECIES

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The long-term objective of this proposal is to achieve an understanding of species differences in response to chemical carcinogenesis. Such an understanding is essential in order to assess the risk to man of a variety of environmental carcinogens and, in particular, in order to make extrapolations from animal studies to man with any degree of reliability. The proposal focuses on nitrosamines, an ubiquitous class of environmental carcinogens and, in particular, on a group of nitrosamines which are potent pancreatic carcinogens for hamster, but not for rat. These nitrosamines consist of two structural classes, of which N-nitroso(2-oxopropyl)amine (MOP) and N-nitrosobis(2-oxopropyl)amine (BOP) are typical examples. Specific aims are directed toward understanding the species difference in response to these compounds. Work accomplished to date has suggested an essential role for liver in activating these nitrosamines. Using computer simulation as a guide, a pharmacokinetic model of MOP metabolism in hamster hepatocytes is being constructed. Parallel measurements of metabolism and DNA damage, as assessed by alkaline elution, are being used to identify metabolic routes leading to genotoxic intermediates. Efforts will be made to determine the structure of these intermediates, to synthesize them or their precursors, and to test them in culture and in whole animals. A similar study in rats is proposed, with a view to identifying differences crucial to the differing response of pancreas of the two species. Finally, it is proposed to apply the same approaches to the BOP class of compounds, which may or may not have mechanisms of carcinogenesis in common with the MOP class.