Reductive metabolism and DNA binding of misonidazole

Misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol) is an experimental anticancer drug. Reductive metabolism is thought to be important for the cytotoxicity of misonidazole. In this study, the DNA binding of misonidazole was examined after chemical and enzymatic reduction. Under anaerobic conditions, both rat liver microsomes and cytosol catalyzed the reductive metabolism and DNA binding of misonidazole. The misonidazole utilized in these studies was radiolabeled on the side chain. The adduct(s) formed was too unstable for structural analysis. Little or no metabolism of misonidazole was detected in aerobic incubations. Likewise, very little DNA binding occurred in the presence of oxygen. Xanthine oxidase, a model nitroreductase, also was capable of catalyzing the DNA binding of misonidazole. However, unlike the xanthine oxidase catalyzed DNA binding of carcinogenic nitropolycyclic aromatic hydrocarbons, the DNA binding of misonidazole was not increased at slightly acidic pH. The putative reactive intermediate, the N-hydroxylamine, was synthesized by zinc reduction of misonidazole. The DNA binding of the N-hydroxylamine derivative increased with increasing pH. The observed pH dependence of the reactions with DNA is similar to other heterocyclic N-hydroxylamines, but is in contrast to the reactivity of a number of aromatic N-hydroxylamines.