PYRIDINE--ENZYME INDUCTION, METABOLISM, AND TOXICITY

苯、三氯乙烯和乙醇等溶剂 广泛应用于各种工业和科研实验室 设置。易挥发的含氮碱，其中吡啶是 原型，也被用在这些场景中。事实上，尼古丁， 在环境中最常作为组件出现 香烟烟雾中，含有吡啶氮杂环 半个月。将吡啶代谢成N-氧化物衍生物的方法是 体内重要的生物转化途径，以及一些 氮氧化物被认为是致癌物质。尽管有明确的 吸烟与肺癌和肺癌发病率的关系 头颈部癌症，对药物知之甚少 新陈代谢与药物代谢酶的诱导 鼻腔和肺组织。最近的实验表明， 吡啶，如乙醇、苯和三氯乙烯(尽管 更有效)，诱导细胞色素P-450(P-450LM/3A) 并导致新陈代谢显著增加 乙醇(S)、二甲基亚硝胺和吡啶对吡啶-N- 氧化物产品。尼古丁也被氧化成N-氧化物，而 乙醇预处理提高了N-氧化速率。至 日期，只有有限的信息关于诱导 细胞色素P-450被吡啶等挥发性溶剂 肝外组织。因此，细胞色素(S)P-450的诱导 通过从兔鼻腔制备的微粒体级分中的吡啶， 将对肺、肾组织进行评估。中国人的代谢活动 这些微生物体对各种底物的作用将被评估。 吡啶诱导对GSH-转移酶、UDP-1活性的影响 葡萄糖醛酸基转移酶和环氧化物水解酶将被评估。 仅与氮碱诱导有关的毒性 致癌物二甲基亚硝胺(N- 用于肺和鼻部组织的亚硝基七甲基亚胺)将 通过组织学和生化分析进行研究。电浆 与肝损伤相关的转氨酶水平也将 将被获得。这项调查的结果将提供 细胞色素P-450诱导作用的重要信息 肝外组织，特别是鼻粘膜和肺，以及 诱导对小鼠异体代谢及毒性的影响 这些纸巾。这些研究将构成整体 目的评价年龄、营养状况和 生物反应调节剂对药物代谢、诱导和代谢的影响 对肝外组织的毒性。

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.