Lack of promoting effects of phenobarbital at low dose on diethylnitrosamine-induced hepatocarcinogenesis in TGF-alpha transgenic mice.

Phenobarbital (PB), a rodent non-genotoxic carcinogen, showed hormesis, biphasic effects on rat liver carcinogenesis. To test the hypothesis that the hormesis earlier observed for PB induced hepatocarcinogenesis might also exist in the TGF-alpha transgenic mice model, one which is highly susceptible to carcinogenesis, the carcinogenic or promotion effects of a wide range of phenobarbital (PB) concentrations were investigated. Two weeks after a single i.p. dose of 5 mg /kg bw of diethylnitrosamine (DEN) to 15 day old mice, animals were treated with diet containing PB at doses of 0, 2, 15 or 500 ppm. The incidence and multiplicity of tumors, including hepatocellular adenomas and carcinomas, were significantly increased by the high dose of PB, but no significant difference among the groups receiving 2 and 15 ppm for liver tumors when compared to DEN alone group. The proliferating cell nuclear antigen indices for liver tumors and surrounding hepatocytes in high dose PB treated mice were significantly increased, but no change was noted at the lower doses. The total cytochrome P450 content in the liver was also elevated by 500 ppm of PB, while hepatic 8-OHdG levels demonstrated no significant change. In conclusion, PB at high dose enhances DEN-induced hepatocarcinogenesis in TGF-alpha transgenic mice, but low doses lack any significant effects. One possible mechanism of phenobarbital carcinogenicity might be influenced by cytochrome P450 system exhibiting a strong promoting activity for liver of mice.

Effects of cessation of alcohol exposure on rat hepatocarcinogenesis.

Cessation of long-term alcohol exposure is reported to enhance rat hepatocarcinogenesis. The purpose of the present study was to assess this possibility using glutathione-S transferase placental form (GST-P) positive foci as end point lesions. All rats were treated with a single i.p. injection of diethylnitrosamine (DEN) (200 mg/kg body weight) and then given a MF pellet diet for 2 weeks. Thereafter, the animals were maintained on: alcohol liquid diet in which 36% of total calories were provided by alcohol (5% Al diet) for 6 weeks (group 1); control liquid diet (C diet) for 6 weeks (group 2); 5% Al diet for 6 weeks and subsequently C diet for 4 weeks (group 3); 5% Al diet for 10 weeks (group 4); or C diet for 10 weeks (group 5). All rats were subjected to two thirds partial hepatectomy at 3 weeks after DEN injection. The number and area of GST-P positive foci per cm2 of liver tissue were slightly increased in group 1 compared to the group 2 and significantly elevated in the group 4 compared to group 5. However, numbers in group 3 were significantly lower in group 4 and similar to the group 5 values. PCNA positive cells in the GST-P positive foci in the group 1 and group 4 were significantly increased as compared with respective controls (groups 2 and 5, respectively), while indices in the group 3 were again similar to values for group 5. Cessation of short-term alcohol administration thus had no promoting effects on development of GST-P foci, suggesting that the duration of alcohol treatment may be important. The results also imply the existence of a cumulative exposure time or dose threshold for alcohol if promoting effects of cessation are to be seen on rat hepatocarcinogenesis.