Detection of a Reactive Metabolite of Misonidazole in Hypoxic Mammalian Cells

metabolism has a role in the biological effects of the drug. In hypoxic cells, reduction of the nitro group is the major metabolic alteration of misonidazole (15). The amine derivative of misonidazole has been shown to be a metabolite of misonidazole (16). Since reduction of nitro compounds proceeds through reactive intermediates such as the nitroso and hydroxylamine intermediates, one possible mechanism for the biological effects of misonidazole is the modification of cell constituents by reduction metabolites. The presence of nitroreduction products of misonidazole associated with the DNA, RNA, and protein fractions in CHO cells after exposure to misonidazole in hypoxia supports such a mechanism (17, 18). In a recent study (19) we have shown that misonidazole after reduction to the hydroxylamine state reacts with guanosine to form a product (Product I) with the structure shown in Fig. 1. In the present study, the formation of Product I has been used to demonstrate that cellular reduction of misonidazole gives rise, at least in part, to the same reactive derivative as that formed by chemical reduction of misonidazole.