Effects of phenobarbital pretreatment on the hepatotoxicity of carbon tetrachloride

Male rats were given daily intraperitoneal injections of phenobarbital (100 mg/kg) in physiologic saline. Their controls received saline alone. After either 3 or 10 successive days of treatment, there was ultrastructural evidence of a marked proliferation of smooth endoplasmic reticulum in the hepatic parenchyma of the drug-injected animals. Such phenobarbital injections also effected significant reductions in hexobarbital-induced sleeping times. These reductions were thought to reflect enhancement of hepatic drug-metabolizing enzyme activity in the phenobarbital-treated groups. Similarly prepared phenobarbital- and saline-injected rats were then challenged with a single dose of carbon tetrachloride (CCl₄) (0.5 ml of a 50% solution in olive oil). Controls received pure olive oil, and they displayed no adverse effects. The CCl₄ treatment, however, produced a 60% mortality over a 4-day period in the phenobarbital-pretreated rats, but only a 4% mortality, complete within 2 days, in the saline-pretreated animals. Phenobarbital-CCl₄- and saline-CCl₄-injected rats were then killed at intervals of 1 1 2, 3, 6, 12, 18, 24, 48, 72, and 96 hours after the toxic challenge. Histologic study of the livers of these animals revealed that parenchymal necrosis evolved more slowly in the phenobarbital-pretreated rats than in the saline-pretreated animals. Ultimately, however, the extent of CCl₄-induced liver necrosis was much greater in drug-pretreated rats than in their saline-pretreated counterparts, i.e., massive or submassive hepatic necrosis in the former vs. a limited centrilobular lesion in the latter. Thus phenobarbital pretreatment delayed the onset of, but ultimately enhanced, CCl₄ hepatotoxicity. It was considered that this altered hepatotoxic response might be related either to the increase of smooth-surfaced membranes or to the augmentation of drug-metabolizing enzyme systems in the livers of the phenobarbital-pretreated animals.