Paradoxical effects of phenobarbital on hepatocarcinogenesis and hepatocytic apoptosis.

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Phenobarbital (PB) is the first discovered tumor promoter for rodent livers in terms of the two-stage or initiation-promotion concept of carcinogenesis. In rats and mice initiated with genotoxic carcinogens, phenobarbital has been shown to increase the number of hepatocellular tumors by approximately 5-fold despite its non-genotoxicity.Importantly, however, it has been also known that, in mice, PB occasionally exhibits strong inhibitory effects on hepatocarcinogenesis initiated with a potent carcinogen, diethylnitrosamine (DEN). For example, while PB enhances development of liver tumors in B6C3F1 mice initiated with DEN as adults, it strongly inhibits hepatocarcinogenesis in the same mice initiated with DEN in their infancy. Such paradoxical outcomes of PB treatment in mice would raise a serious issue when extrapolating the experimental risk data of laboratory animals to human cases.In this study, I provided evidence that the paradoxical actions of PB on hepatocarcinogenesis can be resolved considering qualitative diversity of initiated lesions and their differential responses to phenobarbital promotion. Thus, I propose that the classical two-stage concept should be reconsidered in terms of qualitative heterogeneity of initiation.I also found that PB induces apoptosis in mouse hepatocytes in culture cooperating with c-myc overexpression. This is an unexpected phenomenon, because PB has been regarded as an inhibitor on hepatocytic apoptosis. The PB-induced apoptosis was accompanied by a 10-fold increase in Bax, an apoptotic protein.Consequently, biological effects of PB are quite complicated and clearly need further analysis on their molecular mechanisms.