Further observations upon the effects of phenobarbital pretreatment on the hepatotoxicity of carbon tetrachloride

Male rats received injections of phenobarbital on each of 4 successive days, while controls were given saline. At 1 day after the last injection, phenobarbital-treated rats displayed a marked proliferation of hepatic smooth endoplasmic reticulum and a significant reduction in hexobarbital-induced sleeping time. When phenobarbital- and saline-treated rats were tested at 8 days after their last injection, there was no difference in sleeping times, but hepatic smooth endoplasmic reticulum was still abundant in the drug-treated animals. When phenobarbital-treated rats were given carbon tetrachloride (CCl₄) at 1 day after their last drug injection, there followed a 77% mortality and the livers of such animals showed massive or submassive hepatic necrosis. If the CCl₄ challenge was delayed until the eighth day after the last phenobarbital treatment, there was no mortality and the livers of such rats exhibited only a limited centrilobular zone of parenchymal injury, similar to that of the control groups. Those findings indicate that the proliferated hepatic smooth-surfaced membranes per se cannot be held responsible for the observed differences in CCl₄ hepatotoxicity. Rather, the results support the concept that hepatic drug-metabolizing enzyme systems are involved in the hepatotoxic responses to CCl₄ administration.