Liver glutathione depletion induced by bromobenzene, iodobenzene, and diethylmaleate poisoning and its relation to lipid peroxidation and necrosis.
The mechanisms of bromobenzene and iodobenzene hepatotoxicity in vivo were studied in mice. Both the intoxications caused a progressive decrease in hepatic glutathione content. In both instances liver necrosis was evident only when the hepatic glutathione depletion reached a threshold value (3.5-2.5 nmol/mg protein). The same threshold value was evident for the occurrence of lipid peroxidation. Similar results were obtained in a group of mice sacrificed 15-20 hours after the administration of diethylmaleate, a drug which is mainly conjugated with hepatic glutathione without previous metabolism. The correlation between lipid peroxidation and liver necrosis was much more significant than that between covalent binding and liver necrosis. This fact supports the view that lipid peroxidation is the major candidate for the liver cell death produced by bromobenzene intoxication. Moreover, a dissociation of liver necrosis from covalent binding was observed in experiments in which Trolox C (a lower homolog of vitamin E) was administered after bromobenzene poisoning. The treatment with Trolox C, in fact, almost completely prevented both liver necrosis and lipid peroxidation, while not changing at all the extent of the covalent binding of bromobenzene metabolites to liver protein.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001969:Bromobenzenes / Q000378:metabolism / Q000506:poisoning*; D056486:Chemical and Drug Induced Liver Injury; D002839:Chromans / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D007462:Iodobenzenes / Q000378:metabolism / Q000506:poisoning*; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D008298:Maleates / Q000378:metabolism / Q000506:poisoning*; D051379:Mice; D009336:Necrosis; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001969:Bromobenzenes; D002839:Chromans; D007462:Iodobenzenes; D008054:Lipid Peroxides; D008298:Maleates; D011506:Proteins; C031905:iodobenzene; C032036:bromobenzene; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C014476:diethyl maleate; D005978:Glutathione; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid