PYRIDINE--ENZYME INDUCTION, METABOLISM, AND TOXICITY

吡啶——酶的诱导、代谢和毒性

• 批准号: 3086668
• 负责人: Melissa A Runge-Morris
• 金额: $ 6.37万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3086668
• 关键词: biotransformation; chemical carcinogen; cytochrome P450; drug adverse effect; drug metabolism; enzyme mechanism; epoxide hydrolase; laboratory rabbit; nicotine; nitrogen metabolism; nitrosamines; piperidine; pyridine; toxin metabolism; transaminases

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.

溶剂如苯、三氯乙烯和乙醇， 广泛应用于各种工业和研究实验室 设置. 挥发性含氮碱，其中吡啶是 原型，也用于这些设置。 实际上尼古丁， 在环境中最常见的组件 含吡啶氮杂环 部分。 吡啶代谢为N-氧化物衍生物， 体内重要的生物转化途径， 氮氧化物被认为是致癌物质。 尽管有明确的 吸烟与肺癌发病率的关系， 头颈部癌症，对药物知之甚少 药物代谢和诱导药物代谢酶 鼻和肺组织。 最近的实验表明， 吡啶，如乙醇，苯和三氯乙烯（尽管 诱导细胞色素P-450（P-450LM/3A） 并导致代谢的显著增加， 醇、二甲基亚硝胺和吡啶到吡啶-N- 氧化物产品 尼古丁也被氧化成N-氧化物， 乙醇预处理提高了氮氧化速率。 到 日期，只有有限的信息， 细胞色素P-450通过挥发性溶剂如吡啶 肝外组织 因此，细胞色素P-450的诱导 通过吡啶在微粒体组分中制备自兔鼻， 将对肺和肾组织进行评价。 代谢活动 将评估这些微粒体对多种底物的反应。 吡啶诱导对GSH-转移酶、UDP- 葡萄糖醛酸基转移酶和环氧化物水解酶。 与单独的含氮碱诱导和 致癌物质二甲基亚硝胺（N- 用于肺和鼻组织的亚硝基七亚甲基亚胺）将被 通过组织学和生化分析进行研究。 血浆 与肝损伤相关的转氨酶水平也将 获得。 这次调查的结果将提供 细胞色素P-450诱导的重要信息， 肝外组织，特别是鼻粘膜和肺，以及 诱导对异源生物质代谢和毒性的影响 这些组织。 这些研究将构成整体的基础， 目的是评估年龄、营养状况和 生物反应调节剂对药物代谢、诱导和 肝外组织毒性。