Thioacetamide-induced hepatic necrosis. I. Involvement of the mixed-function oxidase enzyme system.
Metabolic activation of thioacetamide (CH3CSNH2) to a toxic metabolite which is responsible for its hepatotoxicity and/or its carcinogenicity has been proposed by a number of investigators. In this investigation thioacetamide and one of its metabolites, thioacetamide sulfine (CH3CSONH2), have been compared for their ability to inhibit hepatic mixed-function oxidase enzymes as well as their ability to induce hepatic necrosis. Thioacetamide sulfine was found to decrease aminopyrine N-demethylation and aniline hydroxylation at a lower dose and at an earlier time after administration than was the case with thioacetamide. In addition, at all doses examined, thioacetamide sulfine produced a more severe centrilobular hepatic necrosis than equivalent doses of thioacetamide. To determine whether the hepatic mixed-function oxidase enzyme system was involved in the biotransformation of thioacetamide and/or thioacetamide sulfine to a hepatotoxic compound(s), the severity of liver damage was examined after the administration of an inducer or inhibitors of hepatic mixed-function oxidase enzyme activity. Phenobarbital pretreatment potentiated the hepatic necrosis produced by both thioacetamide and thioacetamide sulfine. In contrast, pyrazole, SKF 525-A, and cobaltous chloride protected against the hepatic necrosis caused by thioacetamide and thioacetamide sulfine. These data suggest that both thioacetamide and thioacetamide sulfine are activated by hepatic mixed-function oxidase enzymes to a hepatotoxic compound(s). These data also suggest that the hepatotoxicity may be mediated by its metabolism to thioacetamide sulfine which, in turn, is metabolized to an ultimate toxic metabolite.
D000081:Acetamides / Q000009:adverse effects*; D000632:Aminopyrine / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004347:Drug Interactions; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009336:Necrosis; D010088:Oxidoreductases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013452:Sulfonium Compounds / Q000009:adverse effects; D013853:Thioacetamide / Q000009:adverse effects*; D013997:Time Factors
D000081:Acetamides; D000814:Aniline Compounds; D013452:Sulfonium Compounds; D000632:Aminopyrine; D013853:Thioacetamide; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D010634:Phenobarbital