Protective effect of diethyldithiocarbamate and carbon disulfide against liver injury induced by various hepatotoxic agents.
Diethyldithiocarbamate (DTC) and carbon disulfide (CS2), at nearly equimolar oral dose levels, protected mice against liver damage induced by carbon tetrachloride, chloroform, bromotrichloromethane, thioacetamide, bromobenzene, furosemide, acetaminophen, dimethylnitrosamine and trichloroethylene, as evidenced by the suppression of elevations in plasma GPT activity and liver calcium content, and of histopathological alterations. Both agents also prolonged hexobarbital sleeping time and zoxazolamine paralysis time in mice. DTC and SC, alone, given orally, decreased microsomal metabolism of several substrates (aniline, p-nitroanisole, hexobarbital, zoxazolamine, aminopyrine and 3,4-benzopyrene), CC14-induced lipid peroxidation, and cytochrome P-450 content. The loss of microsomal drug-metabolizing enzyme activity was also observed in the experiments in vitro using liver slices and isolated microsomes. Since a characteristic common to such diverse hepatotoxins is that they require metabolic activation before exhibiting hepatotoxicity, the protective mechanisms of DTC and CS2 may involve their interference with the process of metabolic activation of these hepatotoxins. The protective action of DTC may be mediated almost entirely through CS2 when administered orally and at least partly with parenteral administration, since, in CCl4-induced liver injury, DTC was most effective when given orally, while the action of CS2 was less dependent on the route of administration. Thus CS2 and CS2-producing agents in vivo such as dithiocarbamate derivatives and disulfiram may modify toxicological and pharmacological effects of foreign compounds by inhibiting microsomal drug-metabolizing enzyme activity in the liver.
D000818:Animals; D002246:Carbon Disulfide / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D004050:Ditiocarb / Q000627:therapeutic use*; D006591:Hexobarbital / Q000494:pharmacology; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010243:Paralysis / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D012890:Sleep / Q000187:drug effects; D013859:Thiocarbamates / Q000627:therapeutic use*; D013997:Time Factors; D015049:Zoxazolamine / Q000494:pharmacology
D013859:Thiocarbamates; D004050:Ditiocarb; D015049:Zoxazolamine; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D002246:Carbon Disulfide