The major thrust of this reseach is to continue the systematic investigation of intraspecies differences in the metabolism of certain Beta-oxidized notrosamine carcinogens, such as N-nitroso-2,6-dimethylomorpholine (NNDM), N-nitrosobis(2-oxopropyl)-amine (BOP), and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) which exhibit marked differences in carcinogenic potency and organotropy between the rat and hamster. These involve in vivo and in vitro studies in Syrian golden hamsters and Fischer 344 rats treated with NNDM, BOP and HPOP, and include 1) their in vivo metabolism including formation of the putative proximate carcinogens MOP and MHP; 2) the pharmaco-kinetics of their uptake and excretion; 3) formation and identification of major adducts in liver and pancreas; 4) metabolism in primary pancreatic acinar cell and hepatocyte cultures; 5) their in vitro metabolism by subcellualr fractions; 6) their activation by isolated hepatocytes to mutagenic metabolites as assayed by the V79 cell system and the capacity of ancinar and liver cells to repair DNA damage as measured by unscheduled DNA repair; 7) the uptake of BOP and HPOP by isolated pancreatic ancinar cells and their binding to DNA and RNA; and 8) a test of the hypothesis that sulfate ester formation of HPOP may be important in its activation by determining whether modulation of the sulfate pool significantly alters the yield of tumor induced by HPOP in hamsters.
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