title: Metabolic activation of n-butyraldoxime by rat liver microsomal cytochrome P450. A requirement for the inhibition of aldehyde dehydrogenase.
abstract: n-Butyraldoxime (n-BO) is known to cause a disulfiram/ethanol-like reaction in humans, a manifestation of the inhibition of hepatic aldehyde dehydrogenase (AIDH). As with a number of other in vivo inhibitors of AIDH, n-BO does not inhibit purified AIDH in vitro, suggesting that a metabolite of n-BO is the actual inhibitor of this enzyme. In re-examination of the effect of n-BO on blood acetaldehyde levels following ethanol in the Sprague-Dawley rat, we found that pretreatment with substrates and/or inhibitors of cytochrome P450 blocked the n-BO-induced rise in blood acetaldehyde in the following order of decreasing potency: 1-benzylimidazole (0.1 mmol/kg) > 3-amino-1,2,4-triazole (1.0 g/kg) > ethanol (3.0 g/kg) > phenobarbital (0.1% in the drinking water, 7 days) > SKF-525A (40 mg/kg). Rat liver microsomes were shown to catalyze the conversion of n-BO to an active metabolite that inhibited yeast AIDH. This reaction was dependent on NADPH and molecular oxygen and was inhibited by CO and 1-benzylimidazole. Hydroxylamine, postulated by others to be a metabolite of n-BO, inhibited AIDH via a catalase-mediated reaction and not through an NADPH-supported microsome-catalyzed reaction. Using GLC-mass spectrometry, 1-nitrobutane (an N-oxidation product) and butyronitrile (a dehydration product) were identified as metabolites from microsomal incubations of n-BO. However, neither of these metabolic products inhibited AIDH directly or in the presence of liver microsomes and NADPH. We conclude that another NADPH-dependent, cytochrome P450-catalyzed metabolic product of n-BO is responsible for the inhibition of AIDH by n-BO.
authors.affiliation: Medical Research Laboratories, VA Medical Center, Minneapolis, MN 55417.
authors.forename: E G
authors.initials: EG
authors.lastname: DeMaster
authors.forename: B
authors.initials: B
authors.lastname: Redfern
authors.forename: F N
authors.initials: FN
authors.lastname: Shirota
authors.forename: D L
authors.initials: DL
authors.lastname: Crankshaw
authors.forename: H T
authors.initials: HT
authors.lastname: Nagasawa
mesh_terms: D000079:Acetaldehyde / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D019811:Hydroxylamine; D006898:Hydroxylamines / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D009249:NADP; D009570:Nitriles / Q000378:metabolism; D010091:Oximes / Q000378:metabolism* / Q000494:pharmacology; D010100:Oxygen; D051381:Rats
chemical_list: D006898:Hydroxylamines; D009570:Nitriles; D010091:Oximes; C004609:butyraldoxime; D019811:Hydroxylamine; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; C032723:N-butyronitrile; D010100:Oxygen