DNA DAMAGE INDUCED BY PANCREATROPIC NITROSAMINES

点击翻译按钮获取中文摘要

N-Nitroso-2, 6-dimethylmorpholine (NNDM), N-Nitrosobis(2- oxopropyl)amine (BOP), N-Nitrosobis(2-hydroxypropyl)amine (BHP), and N-Nitroso(2-hydroxypropyl) (2-oxopropyl) amine (HPOP) induce tumors of the pancreas, lungs, gallbladder, kidneys and bladder in hamsters and upper respiratory tract, esophagus, liver, and kidney tumors in rats. Organotropy of these carcinogens depends on dose, sex, frequency and route of administration. Differences between species in pancreas carcinogenesis and between sexes in liver carcinogenesis are marked and useful in the elucidation of the mechanism of action of these carcinogens. It is proposed to study the relationships among metabolism, tissue injury and carcinogenesis in rats and hamsters treated mainly with HPOP, but also with NNDM and BHP. The aims of this study are: 1) Develop the methodology to characterize and quantitate DNA adducts which are formed and persist in various tissues of hamsters and rats during continuous administration of NNDM, BHP and HPOP. 2) Design regimens of continuous administration of these carcinogens which will cause a high incidence of pancreatic tumors. 3) Measure labeling of tissue and DNA of target and nontarget organs during treatment of hamsters and rats with radiolabeled nitrosamines, and also evaluate possible relations between tumor induction and persistence of various DNA adducts. 4) Evaluate the rate of repair of various adducts by measuring the decline of their concentration in DNA and tissues of animals treated either with a single dose of carcinogen or continuously for 7 days. 5) Test the capacity of rats and hamsters to metabolize xenobiotics including the carcinogenic nitrosamines following the treatment period. Also test the activity of phase I and phase II enzymes in the liver and the ability of various tissues to repair 06 MeGuanosine following the treatment with carcinogenic nitrosamines. 6) Investigate the levels of adducts and the rate of their repair in component cells of the pancreas and liver of animals undergoing treatment with HPOP or following such treatment. 7) Examine the effect of low protein diet, methionine-deficient diet and inhibitors of sulfation of HPOP on the carcinogenicity of HPOP in hamsters. Evaluate the effect of such treatment on the formation and repair of DNA adducts in various organs of the animals.