[Dose-response relationship of promotion by phenobarbital in rat two-stage hepatocarcinogenesis]

Investigation of the effect of various doses of phenobarbital (PB) in Experiment I (PB dose levels: 0, 38, 75, 150, 300 or 600 ppm) and Experiment II (PB dose levels: 0, 1, 4 or 16 ppm) given to male F344 rats (20 animals/group) in drinking water for 39 weeks after a single intraperitoneal injection of diethylnitrosamine (DEN) was performed using incidence of hepatic tumors and number or area of enzyme-altered foci as end-point lesions. There were no significant differences in the final body weight changes between DEN-initiated PB treatment (DEN+PB) and DEN-initiated (DEN) groups. Dose-dependent increases in the absolute and relative liver weights and in the incidence of hepatic carcinoma were found in the DEN+PB groups treated with 38 ppm PB or above 75 ppm PB or above, respectively. The numbers or areas of gamma-GTP or GST-P positive foci of the liver were increased in the DEN+PB groups treated with 38 ppm PB or above. Additional investigation of 7-ethoxycoumarin o-deethylase (7-ECDE) induction in Experiment III, 7 groups consisting of 3 animals/group being fed water containing PB (0, 1, 4, 16, 75, 300 or 1200 ppm) for 1 week after the initiation of DEN and a further 7 groups (5 rats/group) receiving the same drinking water without DEN treatment, revealed dose-dependent increases of 7-ECDE in the DEN+PB groups and PB groups treated with 16 ppm PB or above. The present studies indicate that the threshold for promotion by PB is 38 ppm.