Differences in reduction of 1,6-dinitropyrene and 1-nitro-6-nitrosopyrene by rat liver cytosolic enzymes and formation of oxygen-reactive metabolites by nitrosoreduction

Abstract

1,6-Dinitropyrene is a carcinogenic environmental pollutant that is activated to a DNA binding species via nitroreduction. The major reduced metabolite of 1,6-dinitropyrene in aerobic incubations with rat liver cytosol is 1-nitro-6-nitrosopyrene, and further reduction of this metabolite results in formation of DNA-reactive species. We were able to separate the nitroreductase activity in rat liver cytosol from the nitrosoreductase activity by gel filtration. The ability of the nitroreductase to reduce 1,6-dinitropyrene was not affected by the presence of oxygen. Reduction of 1-nitro-6-nitrosopyrene is catalyzed by different enzymes and results in formation of metabolites which can react with oxygen. In aerobic incubations with cytosol, this reaction of reduced intermediates with oxygen does not decrease the binding of 1,6-dinitropyrene to DNA. The ability of rat liver enzymes to reduce 1,6-dinitropyrene to reactive intermediates in the presence of oxygen may be an important factor contributing to the potent tumorigenicity of this compound.