Glutathione depletion, lipid peroxidation, and liver necrosis following bromobenzene and iodobenzene intoxication.
NMRI Albino mice, in which the hepatic glutathione (GSH) content was decreased by nearly 50% by either the administration of a pure glucose diet or by starvation, were intoxicated with aryl halides, bromobenzene, and iodobenzene (13 and 9 mmol/kg body weight, respectively, p.o.). After both intoxications, the hepatic glutathione content decreased rapidly to very low values, and liver necrosis, as assessed by serum transaminase levels, occurred in about 45 or 60% of the animals (in the case of bromobenzene or iodobenzene, respectively) after a lag phase of 9 or 6 hr. In both instances liver necrosis was evident only when the hepatic GSH depletion reached a threshold value (3.5-2.5 nmols/mg protein). The same threshold value was evident for the occurrence of lipid peroxidation (measured as both carbonyl functions and conjugated dienes in liver phospholipids). The possibility that the depletion in hepatic GSH level is capable of inducing lipid peroxidation and necrosis could be supported by the fact that similar results were obtained after the administration of inethylmaleate (12 mmol/kg, p.o.), a drug which is expected to conjugate directly with GSH without previous metabolism. The covalent binding of reactive metabolites to cellular macromolecules was determined in the case of bromobenzene poisoning. A dissociation between liver necrosis and covalent binding was observed in experiments in which Trolox C, a lower homolog of vitamin E, was administered (270 mumol/kg) 9 and 13 hr after bromobenzene poisoning. The treatment with Trolox C, in fact, almost completely prevented both liver necrosis and lipid peroxidation, while the extent of the covalent binding of bromobenzene metabolites to liver proteins was not altered.
D000818:Animals; D001969:Bromobenzenes / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis*; D007462:Iodobenzenes / Q000633:toxicity*; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000032:analysis / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis
D001969:Bromobenzenes; D007462:Iodobenzenes; D008054:Lipid Peroxides; D008298:Maleates; C031905:iodobenzene; C032036:bromobenzene; C014476:diethyl maleate; D005978:Glutathione