Microsomal metabolism of acetonitrile to cyanide. Effects of acetone and other compounds.
Oral acetone exposure delays and potentiates acetonitrile toxicity in rats. Results of previous pharmacokinetic studies suggested that acetone exerted a biphasic effect on the metabolism of acetonitrile to cyanide; the presence of acetone in vivo appeared to inhibit the metabolism of acetonitrile to cyanide, whereas the disappearance of acetone from serum was followed by stimulation of acetonitrile metabolism. The current experiments were designed to characterize further the metabolism of acetonitrile to cyanide and the effects of acetone and other compounds upon this metabolism. Liver microsomes were isolated and pooled 24 hr after oral pretreatment of female Sprague-Dawley rats (180-250 g) with acetone (1960 mg/kg) or water. Microsomal metabolism of acetonitrile to cyanide was found to be oxygen and NADPH dependent, and heat-inactivated tissue was unable to catalyze the reaction. NADH antagonized the NADPH-dependent metabolism of acetonitrile. The metabolism of acetonitrile to cyanide was linear with protein concentrations of 0-8 mg per incubation. Following a characteristic lag period of 10 min, the reaction was linear from 15 to 30 min. This metabolism was inhibited by carbon monoxide, metyrapone and SKF 525-A. Acetone pretreatment (-24 hr) in vivo increased the apparent Vmax for acetonitrile metabolism without affecting the apparent Km. When added in vitro, acetone competitively inhibited the metabolism of acetonitrile, with a KI of 0.41 mM. Dimethyl sulfoxide (KI = 0.51 mM) and ethanol (KI = 0.11 mM) were also competitive inhibitors of acetonitrile metabolism, and aniline HCl (KI = 4.77 microM) appeared to be a mixed inhibitor. These data are consistent with the hypothesis that the metabolism of acetonitrile to cyanide is mediated by a specific acetone-inducible isozyme of cytochrome P-450.
Freeman
J J
JJ
Department of Environmental and Community Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway.
Hayes
E P
EP
D000096:Acetone / Q000494:pharmacology*; D000097:Acetonitriles / Q000378:metabolism*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology; D003486:Cyanides / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011506:Proteins / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000097:Acetonitriles; D000814:Aniline Compounds; D003486:Cyanides; D011506:Proteins; D009243:NAD; D000096:Acetone; D000431:Ethanol; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C023650:aniline; D004121:Dimethyl Sulfoxide; C032159:acetonitrile; D008797:Metyrapone