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.
Kohl
C
C
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
Schiller
C D
CD
Gescher
A
A
Farmer
P B
PB
Bailey
E
E
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D009153:Mutagens / Q000378:metabolism*; D009595:Nitroparaffins / Q000302:isolation & purification / Q000378:metabolism*; D010091:Oximes / Q000378:metabolism*; D011407:Propane / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D002273:Carcinogens; D009153:Mutagens; D009595:Nitroparaffins; D010091:Oximes; C069720:propane-2-nitronate; D003577:Cytochrome P-450 Enzyme System; C035911:acetoxime; D011407:Propane