THE MECHANISM OF REDUCTION OF TOXIC CHEMICALS AND DRUGS

减少有毒化学品和药物的机制

• 批准号: 3841111
• 负责人: R P MASON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3841111
• 关键词: cell membrane; drug metabolism; electron spin resonance spectroscopy; heterocyclic compounds; ion transport; liver; liver metabolism; nitrogen compounds; pyridine; reduction; toxin metabolism; cell membrane; drug metabolism; electron spin resonance spectroscopy; heterocyclic compounds; ion transport; liver; liver metabolism; nitrogen compounds; pyridine; reduction; toxin metabolism

The first step in the metabolic conversion of many chemicals and toxic drugs is the reduction of the parent compound to give a free radical intermediate. This metabolism has been shown to occur in both liver microsomes and hepatocytes. For nitroheterocyclic drugs, the nitro group is reduced to the corresponding nitro radical anion and for bipyridylium dictations, the parent compound is reduced to the bipyridylium radical monocation. By judicious application of paramagnetic line broadening agents, we have shown that the radicals, initially formed inside the cell can freely cross the plasma membrane, and the EPR signal detected is mainly due to radical present extracellularly. Recently, the laboratory purchased a Krumdieck tissue slicer. This type of slicer has been shown to produce reproducibly thin slices with maximal slice integrity. Liver slices, unlike microsomes or hepatocytes, contain a cross section of all liver cells and the results are more physiologically similar to in vivo liver metabolism. This is the first such EPR application to organ slices which has not been lyophilized or encased in paraffin supports. Preliminary experiments with bipyridylium dictations have shown that it is possible to detect free radical intermediates in thin liver slices and that the radical generated is in a more viscous environment than with either microsomes or hepatocytes. In the coming year, we will continue this line of investigation and extend the experiments to include nitroheterocyclic compounds.

许多化学物质和有毒的代谢转化率的第一步 药物是父母化合物的还原以提供自由基 中间的。 这种新陈代谢已显示出在两个肝脏中发生 微粒体和肝细胞。 对于硝基细胞药物，氮组 还原为相应的硝基自由基阴离子和双吡啶基 约束，将母体化合物还原为双吡啶基自由基 单调。 通过明智地应用顺磁线扩展 代理，我们已经表明，最初形成的自由基在细胞内形成 可以自由地越过质膜，并且检测到的EPR信号主要是 由于根本存在细胞外。 最近，实验室购买了 Krumdieck组织切片机。 这种类型的切片机已显示出生产 具有最大切片完整性的可重复性薄片。 肝切片， 与微粒体或肝细胞不同，包含所有肝脏的横截面 细胞和结果在生理上与体内肝脏更相似 代谢。 这是第一个在器官切片中的EPR应用 尚未被冻干或包裹在石蜡载体中。 初步的 双吡啶基概念的实验表明，有可能 检测薄肝切片中的自由基中间体，并从 与微粒体或 肝细胞。 在来年，我们将继续这条线 调查并扩展实验以包括硝基粒细胞 化合物。