Paradoxical effects of phenobarbital on mouse hepatocarcinogenesis

Phenobarbital was the first tumor promoter for rodent liver to be associate d with the 2-stage or initiation-promotion concept of carcinogenesis. In ra ts and mice preinitiated with genotoxic carcinogens, phenobarbital administ ration increases the number of hepatocellular tumors by approximately 5-fol d despite its nongenotoxicity. However, in mice phenobarbital occasionally exhibits strong inhibitory effects on hepatocarcinogenesis initiated with t he potent carcinogen diethylnitrosamine. Both positive and negative effects of phenobarbital on hepatocytic proliferation and apoptosis, which are mec hanistically involved in the promotion stage of hepatocarcinogenesis, have been described. These complex outcomes of phenobarbital treatment and their effects on hepatocarcinogenesis in mice raise serious issuer regarding ext rapolation of experimental data from laboratory animals to human risk asses sment. Recent work suggests that the paradoxical actions of phenobarbital o n hepatocarcinogenesis can be understood by consideration of qualitative di versity in initiated lesions and differential responses to promotion stimul us.