Nitrogenous bases such as pyridine are widely used as reagents and solvents in a variety of industrial and laboratory settings. Pyridine is employed as an intermediate in the manufacture of drugs, explosives, paints, disinfectants, fungicides, insecticides, herbicides, and as a denaturant for alcohol. Recent work in our laboratory has shown pyridine to be a potent inducer of hepatic microsomal cytochrome P-450 as evidenced by a 2-fold increase in P-450 content relative to uninduced microsomes and a 4-fold to 10-fold enhancement in dimethylnitrosamine, alcohol, and aniline metabolism. Benzo[a]pyrene hydroxylase and pyridine N-oxidase activities are also significantly enhanced. The electrophoretic pattern of pyridine-induced microsomes shows protein bands of enhanced intensity occurring in the region of P-450LM2, LM4, and LM6. To date, there is no information on the ability of pyridine to induce P-450 and metabolic activity in extrahepatic tissues such as the nose, lung, or kidney which may be exposed to this agent during absorption and excretion. Moreover, no information is available on pyridine-induction of non-P-450 drug metabolizing enzymes (GSH transferase, epoxide hydrolase, UDP-glucuronyltransferase) in hepatic or extrahepatic tissue. Finally, little is known about xenobiotic-mediated toxicity to tissues as a consequence of pyridine induction in affected tissues. In view of the physicochemical properties of pyridine, the finding that it induces cytochrome P-450(s) active in carcinogen metabolism, and the toxicologic significance associated with enhanced metabolic activity, we propose: 1) to examine exposure regimens for induction of drug metabolizing enzymes in rabbit nasal, lung, kidney and liver tissue; 2) to characterize the metabolic activity of nitrogenous base-induced rabbit nasal, lung, kidney, and liver cytosolic and microsomal preparations; 3) to evaluate the effect of pyridine induction of drug metabolizing enzymes on toxicity in vivo; and 4) to evaluate the propensity of other nitrogenous bases to induce drug metabolizing enzymes in rabbit nasal, lung, kidney, and liver tissue. UV-visible difference spectroscopy, SDS-PAGE, and standard metabolic assays will be employed in the characterization of induction and metabolic activity. The induction of cytochrome P-450 by volatile, water-soluble nitrogenous bases such as pyridine (which are readily absorbed through inhalation or ingestion) may result in a profound effect on toxicity of xenobiotics and on tissue susceptibility to tumorigenesis.
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