PYRIDINE--ENZYME INDUCTION, METABOLISM, AND TOXICITY

溶剂如苯、三氯乙烯和乙醇

Solvents such as benzene, trichloroethylene, and ethanol are widely employed in a variety of industrial and research laboratory settings. Volatile nitrogenous bases, for which pyridine is prototypic, are also utilized in these settings. Indeed nicotine, most commonly encountered in the environment as a component of cigarette smoke, contains the pyridine nitrogen heterocycle moiety. The metabolism of pyridine to an N-oxide derivative is an important biotransformation pathway in vivo, and some nitrogen oxides have implicated as carcinogens. Despite a clear association of cigarette smoking and the incidence of lung and head and neck cancer, relatively little is known regarding drug metabolism and the induction of drug metabolizing enzymes in nasal and lung tissues. Recent experiments have revealed that pyridine, like ethanol, benzene, and trichloroethylene (although much more potently), induces cytochrome P-450 (P-450LM/3A) and results in a substantial increase in the metabolism of alcohol(s), dimethylnitrosamine and pyridine to the pyridine-N- oxide product. Nicotine is also oxidized to an N-oxide and the rate to N-oxidation is increased by ethanol pretreatment. To date, there is only limited information on the induction of cytochrome P-450 by volatile solvents such as pyridine in ectrahepatic tissues. Thus, the induction of cytochrome(s) P-450 by pyridine in microsomal fractions prepared from rabbit nasal, lung, and kidney tissues will be evaluated. Metabolic activity in these microsomes towards a variety of substrates will be assessed. The effect of pyridine induction on GSH-transferase, UDP- glucuronyltransferase, and epoxide hydrolase will be evaluated. Toxicity associated with nitrogenous base induction alone and in the presence of carcinogen dimethylnitrosamine (N- nitrosoheptamethyleneimine for lung and nasal tissues) will be studied via histologic and biochemical analysis. Plasma transaminase enzyme levels correlative to hepatic injury will also be obtained. The results of this investigation will provide important information on the induction of cytochrome P-450 in extrahepatic tissues, particularly the nasal mucosa and lung, and the effects of induction on xenobiotic metabolism and toxicity in these tissues. These studies will form the basic for the overall objective of evaluating the effect of age, nutritional status, and biologic response modifiers on drug metabolism, induction and toxicity in extrahepatic tissues.