The metabolism, including absorption, distribution in the body, interaction with cellular constituents, and excretion, of a number of selected N-nitroso compounds and their metabolic products will be studied in rats and other species. The N-nitroso compounds will include nitrosamines, nitrosamides and nitrosamidines as well as methylhydrazines and phenyldimethyl-triazene. Most of the compounds chosen are carcinogenic but some are reported to be noncarcinogenic. Emphasis will be placed on nitrosamides that are used in clinical human cancer chemotherapy since these are the only N-nitroso compounds that are deliberately administered to human subjects. The compounds will be variously labeled with radioactive (14C and 3H) and stable (15N and 13C) isotopes. Nitrosamines will be measured in tissues and body fluids by a new method of differential pulse polarography that is currently being developed in these laboratories. The metabolism of secondary amines that occur normally in the body, including dimethylamine, pyrrolidine, piperidine, proline and sarcosine, will be studied in relation to their potential endogenous nitrosation under various conditions. The metabolism of nitrate and nitrite will be studied since relatively little is known in this area. Nitrite estimations in tissues and body fluids will be carried out by a new method based on nitrosation of diphenylamine. Nitrite and nitrate labeled with 15N will be used in part of this work. The development and improvement of the new method for nitrosamine and nitrite determination will be a major part of the proposed research. It is hoped that the proposed research will increase knowledge of the role of alkylation reactions in carcinogenesis by nitroso compounds and the possible role that these compounds may play in the causation of animal and human cancer.
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