Effect of chronic phenobarbitone administration on liver tumour formation in the C57BL/10J mouse

Abstract

The hepatocarcinogenicity of sodium phenobarbitone (PB) was studied in male and female mice of the low spontaneous liver tumour incidence C57BL/10J strain. Treatment with 200 and 1000ppmPB for 1 month increased relative liver weight in both sexes, with 1000ppmPB also producing a transient increase in replicative DNA synthesis. The treatment of male and female mice with 200 and 1000ppm (the maximum tolerated dose) PB for 99weeks resulted in centrilobular hypertrophy and a dose-dependent increase in relative liver weight. Altered hepatic foci were observed in both sexes given 1000ppm PB. In male mice given 1000ppm PB significant increases were observed in the incidence of hepatocellular adenoma and carcinoma, to 43% and 10% of the animals examined, respectively. No increase in liver tumours was observed in male mice given 200ppm PB and in female mice given 200 and 1000ppm PB. In summary, PB at a dose level which produces liver hypertrophy, a transient stimulation of replicative DNA synthesis and on chronic administration altered hepatic foci, three key events in the established mode of action for PB-induced rodent liver tumour formation, results in a significant increase in liver tumours in male C57BL/10J mice.