The long-term objective of the proposed research is to use the pig as an animal model to help clarify extrapolation of findings on nitrosamine metabolism and carcinogenesis in rodents to man. Advantages of this species include its greater size, allowing cannulation of the portal and hepatic veins, and the bile duct, from which relatively large samples can be obtained in the conscious animal. The pig resembles man in many aspects of its physiology and is the species of choice as a model for human alcoholi. The project has four specific aims: (1) To study the pharmacokinetics and metabolism of dimethylnitrosamine in pigs and to measure the extents of methylation of DNA of various organs and of blood proteins. The non-radioactive or labeled compound will be given by the oral and intravenous routes and directly into the portal vein by single or repeated injections or by continued infusion. Further experiments will examine N-nitrosopyrrolidine and N-nitrosopiperidine, of which the parent amines occur endogenously, N-nitrosodiethylamine, N-nitrosodiethanolamine and N-nitrosomorpholine, and benzylmethyl-, phenylmethyl- and diphenylnitrosamine. (2) To compare the activating and deactiviting metabolic pathways of the nitrosamines in the intact animal in vivo. The activating pathways are considered to be those leading to alkylating intermediates and deactivation refers to denitrosation, reduction and other pathways. Hepatic venous blood and bile will be analyzed for metabolites identified in in vitro studies. (3) To investigate pigs receiving various human diets and nitrosatable drugs. The diets will be those associated with elevated circulating levels of nitrosamines or those related by epidemiological studies to human cancer. The drugs will include aminopyrine, known to yield dimethylnitrosamine on nitrosation, disulfiram reported to yield diethylnitrosamine, piperazine, and cimetidine which can be nitrosated to yield a methylating mutagen. The nitrosamines will be sought in the blood and tissues of the animals, as will products of their metabolism and macromolecular interaction. (4) To investigate the hypothesis that the association of alcohol with some human cancers may be related to its inhibition of hepatic metabolism of endogenous and/or exogenous nitrosamines, thus increasing the exposure of extra hepatic organs to the carcinogens. The acute and chronic effects of ethanol on the pharmacokinetics and metabolism, and tissue alkylation activities of dimethylnitrosamine and other nitrosamines will be studied.
