Pathways for the bioactivation of aliphatic nitriles to free cyanide in mice.
Reports from several laboratories agree that many, but not all, aliphatic nitriles undergo hepatic biotransformation in mice and rats to release free cyanide, but the mechanisms at work in these reactions remain in doubt. We have used primarily n-butyronitrile, propionitrile, and their respective alpha-carbon-hydroxylated homologs, propionaldehyde cyanohydrin and lactonitrile, to examine this question in mice. Pretreatment of mice with the hepatic microsomal enzyme inducers, pregnenolone-16 alpha-carbonitrile, troleandomycin, and isosafrole, or with the cytochrome P-450-depleting agent, cobaltous chloride, did not influence the mortality of mice given single doses of nitriles. Repeated injections of aspirin or sodium salicylate in water failed to protect mice against death by the nitriles. Dimethyl sulfoxide, however, was effective in reducing mortality after nitrile administration. Repeated injections of 4-methylpyrazole or disulfiram protected mice against death after nitriles. Most of the treatment regimens successful against the nitriles also protected against death due to the cyanohydrins. The cyanohydrins were more acutely toxic than their parent nitriles, produced death much more rapidly, and resulted in the same toxic signs, suggesting that they are intermediates in the bioactivation pathway leading to free cyanide. The cyanohydrins appeared to serve as weak substrates for yeast alcohol dehydrogenase, however, incubation of them with either yeast or horse liver alcohol dehydrogenase did not increase the rate of cyanide release over that in incubations where the enzymes were absent. The slow rate of cyanide release due to spontaneous hydrolysis interfered with the determinations of alcohol dehydrogenase activity, but it cannot account for the rapid action and high toxicity of the cyanohydrins in vivo, or for the efficacy of the treatment regimens which protected against death. It appears unlikely that prostaglandin synthetase or alcohol dehydrogenase are importantly involved in nitrile bioactivation. The same active process, however, appears to be responsible both for alpha-carbon hydroxylation and for the subsequent degradation of the resulting cyanohydrins to release free cyanide. It is far more efficient in mediating the latter reaction than the former.
D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003486:Cyanides / Q000037:antagonists & inhibitors; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D000077604:Fomepizole; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism* / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012459:Salicylates / Q000494:pharmacology; D013379:Substrate Specificity
D003486:Cyanides; D009570:Nitriles; D011720:Pyrazoles; D012459:Salicylates; D000077604:Fomepizole; D006899:Mixed Function Oxygenases; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase; D011451:Prostaglandin-Endoperoxide Synthases; D004221:Disulfiram; D004121:Dimethyl Sulfoxide