THE MECHANISM OF REDUCTION OF TOXIC CHEMICALS AND DRUGS

许多化学物质和有毒物质代谢转化的第一步 药物是母体化合物的还原，产生自由基 中级的。这种新陈代谢已被证明发生在两个肝脏。 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阴离子，对于联吡啶 口述，母体化合物被还原为联吡啶基 单点定位。通过合理应用顺磁线展宽 试剂，我们已经证明，最初在细胞内形成的自由基 可以自由穿越质膜，检测到的EPR信号主要 由于激进分子存在于细胞外。最近，该实验室购买了 克鲁姆迪克组织切割机。这种类型的切片机已经被证明可以生产 可复制的薄片，具有最大的切片完整性。肝脏切片， 与微粒体或肝细胞不同，它包含所有肝脏的横切面 细胞和结果在生理上更类似于活体肝脏 新陈代谢。这是第一次将EPR应用于器官切片 未经冷冻干燥或包裹在石蜡载体中。初步 用联吡啶口述的实验表明，有可能 检测肝脏薄片中的自由基中间体和自由基 是在更粘稠的环境中产生的，而不是微粒体或 肝细胞。在未来的一年里，我们将继续这条线 调查和扩展实验以包括硝基杂环化合物 化合物。

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.