Metabolism and excretion of [3H]misonidazole by hypoxic rat liver.

Our investigation was initiated to determine if misonidazole's biological activity is related to hypoxia-dependent, reductive biotransformation to form reactive metabolites. This study was facilitated by the synthesis of [3H]misonidazole and by use of the isolated perfused rat liver as a model system for hypoxic tissue. The perfused rat liver was verified as an appropriate model system to study misonidazole (MISO) metabolism. This was done by demonstrating that the perfused liver produced the same metabolites as those isolated from rats given MISO, albeit reductive metabolism was much less in rats. Reductive metabolism of MISO by perfused livers was enhanced (estimated by measuring the rate of 1-[2-aminoimidazol-1-yl]-3-methoxy-2-propanol production) by hypoxic conditions. Formation of a MISO-derived glutathione conjugate (MISO-GSH) and covalent binding of MISO-derived radioactivity to tissue protein was also enhanced by hypoxia. Depletion of hepatic GSH with diethyl maleate increased the extent of covalent binding to protein under both aerobic and hypoxic conditions, and greatly diminished the formation of MISO-GSH. These results support the hypothesis that hypoxic conditions facilitate reductive metabolism of MISO to an alkylating agent, and that GSH plays an intervening role in the alkylation reaction.