This laboratory has previously postulated that bromobenzene-induced hepatic necrosis results from the formation of a reactive metabolite that arylates vital cellular macromolecules. Accordingly, the severity of liver necrosis has been compared with the formation of metabolites of bromobenzene and with covalent binding of metabolites in vivo and in vitro after various pretreatment regimens that alter hepatotoxicity. These data provide direct kinetic evidence that 3,4-bromobenzene oxide is the reactive hepatotoxic metabolite. The studies also demonstrate that the hepatotoxic metabolite is preferentially conjugated (detoxified) with glutathione, thereby depleting glutathione from the liver. Liver necrosis and arylation of cellular macromolecules occur only when glutathione is no longer available. Thus, a dose threshold exists for bromobenzene-induced hepatic necrosis.

Recent studies of acetaminophen-induced liver damage in animals indicate 676vital hepatocellular macromolecules. 9 , 18 Pretreatment with inducers of metabolism, such as phenobarbital, increases the rate of metabolism of acetaminophen, the extent of hepatic binding of radio labeled metabolite, and the severity of hepatic necrosis.!" 13. 15. 18 Conversely, pretreatment with inhibitors of metabolism markedly decreases the metabolism of acetaminophen, the covalent binding, and the hepatic necrosis.!)' 1:1, 15, 18 A direct relationship has also been demonstrated between the formation of an acetaminophen-gluthathione conjugate, arylation of hepatic macromolecules, and hepatic damage after administration of acetaminophenY, 16·18 After nontoxic doses of