THE MECHANISM OF REDUCTION OF TOXIC CHEMICALS AND DRUGS

许多化学物质和有毒药物代谢转化的第一步是 母体化合物还原生成自由基中间体。 这种代谢已被证明发生在肝微粒体和 肝细胞 对于硝基杂环药物，硝基被还原为 相应的硝基自由基阴离子，对于联吡啶基， 母体化合物被还原成联吡啶基一价阳离子。 通过 顺磁性谱线增宽剂的明智应用，我们已经表明， 最初在细胞内形成的自由基可以自由地穿过细胞， EPR信号主要是由于自由基的产生， 存在于细胞外。 最近，实验室购买了一台Krumdieck 组织切片机 这种类型的切片机已被证明是可重复生产的 具有最大切片完整性的薄切片。 肝切片，不像微粒体 或肝细胞，包含所有肝细胞的横截面， 在生理上更类似于体内肝脏代谢。 这是 第一次将这种EPR应用于未冻干的器官切片 或包裹在石蜡载体中。 联吡啶酮的初步实验 口述表明，它是可能的，检测自由基 中间体在薄肝切片和自由基产生的是在一个 比微粒体或肝细胞更粘稠的环境。 在 在未来一年，我们将继续这方面的调查，并扩大 实验包括硝基杂环化合物。

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.