Lack of correlation between hepatic prostaglandin concentrations and DNA synthesis after the administration of phenobarbital and the peroxisome proliferator ciprofibrate in rats

Peroxisome proliferators are a class of chemicals that induce and promote hepatic tumors in rodents. These compounds are not genotoxic, and the mechanism by which they induce and promote tumors is poorly understood. Phenobarbital (PB) also is a hepatic tumor promoter that produces a different natural history than peroxisome proliferators during the promotion of hepatocarcinogenesis. In addition, opposite effects on hepatic eicosanoid concentrations have been demonstrated previously. In this experiment, we examined whether higher hepatic eicosanoid concentrations correlated with the induction of DNA synthesis after the administration of PB or the peroxisome proliferator ciprofibrate (CIP). PB (0.05% in diet) or CIP (0.01% in diet) was fed to rats from 1-10 days. For the rats treated with CIP, the peroxisomal enzyme fatty acyl-CoA oxidase increased gradually from day 1 to day 10. PB treated rats had a higher cytochrome P450 2B1/2 activity over the entire course of feeding. Hepatic prostaglandins E₂ and F(2α) concentrations were significantly reduced in the rats treated with CIP, while no significant differences were seen between the control and PB-treated rats. DNA synthesis was increased in both PB-treated and CIP-treated rats. These results show that higher eicosanoid concentrations do not correlate with the induction of hepatic DNA synthesis by CIP or PB.