EFFECT OF PHENOBARBITAL ON HEPATIC EICOSANOID CONCENTRATIONS IN RATS

Phenobarbital is an efficacious tumor-promoting agent in the liver. St udies using inhibitors of eicosanoid synthesis have suggested that eic osanoids are important in the promotion of hepatocarcinogenesis by phe nobarbital. We therefore hypothesized that hepatic eicosanoid concentr ations are altered following phenobarbital administration. Male Spragu e-Dawley rats were fed one of four levels of phenobarbital (0, 0.02, 0 .05, and 0.1%). Eight rats from each of the four groups were killed af ter 10, 24, and 44 days for determination of liver weight and for prep aration of microsomes, No significant difference was found among rat w eights; however, liver weights were significantly higher in rats fed p henobarbital. Assay of benzyloxyresorufin-O-dealkylase activity showed that cytochromes P-450 2B1 and 2B2 were induced in response to phenob arbital administration. Prostaglandin E-2 concentrations were found to be significantly decreased by phenobarbital treatment after 10 and 24 days, but not after 44 days. Prostaglandin F-2 alpha levels were decr eased only by the lowest dietary phenobarbital concentration. Hepatic concentrations of leukotriene C-4 were decreased significantly at 10 d ays and at 44 days (only for the group administered the highest percen tage concentration of phenobarbital), but not at 24 days. These result s show that the investigated eicosanoids are generally slightly decrea sed by phenobarbital administration. Elevated eicosanoid levels theref ore do not appear to be necessary for the promoting activity of phenob arbital.