Determination of the factors which influence susceptibility to chemical carcinogens and of means of modulating this susceptibility are important goals. Such factors have been studied in several animal model systems, with particular emphasis on metabolism of carcinogens and on tumor initiation and promotion. (1) The metabolism, distribution, toxicity, and carcinogenic effects of the environmental agent, N- nitrosodimethylamine (NDMA), in the mouse have been found to be significantly altered by co-administration of ethanol in the drinking water. The presence of ethanol resulted in reduced toxicity in liver but increased circulating levels of NDMA and, importantly, led to an increase in lung tumors. Experiments are in progress to distinguish between pharmacokinetic (dose delivery), cellular (repair of DNA damage), and tumor promotion mechanisms of this effect. (2) N-nitrosocimetidine (NMC), a derivative of a commonly-used pharmaceutical, though not a complete carcinogen, has been found to be a tumor initiator on mouse skin, giving rise to papillomas and carcinomas on about half of mice for which skin treatment with NCM has been followed by the tumor promoter, tetradecanoylphorbol acetate (TPA). (3) An immunohistochemical study with a specific monoclonal antibody to isozymes of cytochrome P450 induced by polycyclic aromatic hydrocarbons (PAH) has revealed that this procedure can be used for semiquantitative determination of metabolic phenotype of liver, and that in extrahepatic tissues, staining is especially intense in, and perhaps limited to, the endothelium of the capillaries, a finding of considerable potential importance in the context of vascular disease, as well as cancer etiology. (4) A related project is extending investigations of protection against carcinogenesis by enzyme induction and employs the environmental carcinogen, benzo(a)pyrene, with the direct-acting carcinogen, N- nitrosoethylurea, as control. (5) Measurements are in progress of the metabolism of NDMA by several murine tissues as a function of inducer and age and include kinetic analysis and use of monoclonal antibodies as biochemical probes to distinguish different isozymes of cytochrome P-450.
