The purpose of the proposed research is to elucidate the pathways for the metabolism and metabolic activation of N-nitroso-2, 6-dimethylmorpholine in Syrian golden hamsters and Sprague-Dawley rats in an attempt to delineate the key differences in the metabolism of this carcinogen which may be responsible for the significant difference in the carcinogenic effect of this compound in the two species.
The specific aims of this proposal are: 1) to investigate interspecies variations in the hepatic and pancreatic metabolism of the nitrosamine i vivo by Syrian golden hamsters and Sprague-Dawley rats; 2) study the hepatic and pancreatic metabolism of N-nitroso-2, 6-dimethylmorpholine and selected metabolites using tissue homogenates and subcellular fractions from rats and hamsters; 3) characterize the activation of the nitrosamine to mutagenic intermediates by isolated pancrease cells and homogenates using the Chinese hamster V-79 mutagenesis assays; 4) determine the cellular location of the pancreatic enzymes involved in the metabolism of the nitrosamine carcinogen; and 5) characterize and identify the liver and pancreatic enzymes responsible for nitrosamine metabolism. The information obtained from these studies should further our knowledge of the sequence of events involved in the metabolic activation of N-nitroso-2, 6-dimethylnitrosomorpholine to its ultimate carcinogenic form in the hamster pancreas, the identity of the enzymes responsible for both the activation and detoxication of this compound, and should help to elucidate the mechanism(s) of carcinogenesis by this compound. These results could ultimately prove to be of value in developing strategies for the prevention of human pancreatic cancer.
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