THE MECHANISM OF REDUCTION OF TOXIC CHEMICALS AND DRUGS

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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.