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.