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: 3855932
• 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/3855932
• 关键词: cell membrane; drug metabolism; heterocyclic compounds; ion transport; liver; liver metabolism; nitrogen compounds; pyridine; reduction; toxin metabolism

The first step in 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 dications, 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 produced 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 have 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 nitoheterocyclic compounds.

许多化学物质和有毒药物的代谢转化率的第一步是 父级化合物的还原以产生自由基中间体。 这种新陈代谢已显示出在肝微粒体和 肝细胞。 对于硝基粒细胞药物，硝基组还原为 相应的硝基自由基阴离子和双吡啶基分离， 母体化合物降低至双吡啶基自由基单位差。 经过 我们已经表明，明智地应用顺磁线扩展剂 最初形成在细胞内部的自由基可以自由地越过 质膜，检测到的EPR信号主要是由于自由基 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可重复产生的 薄片具有最大切片完整性。 肝切片，不同于微粒体 或肝细胞，包含所有肝细胞的横截面，结果 在生理上与体内肝脏代谢更相似。 这是 首先将这种EPR应用于尚未冻干的器官切片 或包裹在石蜡支撑中。 双吡啶基的初步实验 说法表明，可能有可能实现自由基 薄肝切片中的中间体，产生的自由基在 与微粒或肝细胞相比，粘性环境更多。 在 来年，我们将继续进行这一调查，并扩展 实验以包括硝基细胞化合物。