Acetoxime is metabolized by human and rodent hepatic cytochrome P450 enzymes to the genotoxicant and carcinogen propane 2-nitronate

The hepatocarcinogenicity of acetoxime has been tentatively linked with its metabolic oxidation to the potent genotoxicant and carcinogen propane 2-nitronate (P2-N). In order to test the hypothesis that acetoxime is metabolized to P2-N, the oxime (20 mM) was incubated with liver microsomes from mice, rats and two humans. Ion-pair HPLC analysis of the incubates afforded a peak that co-eluted with P2-N. P2-N exists in tautomeric equilibrium with 2-nitropropane (2-NP). Samples of the microsomal incubates, which had been adjusted to pH 5.5 and kept for 24 h in order to allow maximal tautomeric equilibration of P2-N to 2-NP to occur, were extracted with hexane. GLC analysis of the extracts yielded a peak that co-eluted with 2-NP, and gave a mass spectrum identical to that of authentic 2-NP. The metabolite peak obtained on HPLC was isolated and its hexane extract contained also 2-NP when investigated by GLC. P2-N was found by HPLC in the urine of rats that had received acetoxime (3.36 mmol/kg i.p.). Hexane extracts of urine samples, which had been adjusted to pH 5.5 and left for 24 h, contained 2-NP as demonstrated by GLC analysis. The results are consistent with the suggestion that the toxicity of acetoxime is associated with its biotransformation to P2-N.