Abstract
The dose-dependent promoting effect of phenobarbital (PB) on rat 2-stage hepatocar-cinogenesis was investigated. Male F344 rats were given 600, 300, 150, 75 or 38ppm PB solutions ad libitum as their drinking water for 39 weeks following initiation with a single intraperitoneal injection of diethylnitrosamine (DEN) (100mg/kg). At week 40, the incidences of hepatic tumors were increased significantly in the DEN+PB groups given 300ppm and 600ppm PB, as compared to that in the DEN group. Linear dose-response curves for numbers and sizes of enzyme altered foci (γ-GTP or GST-P positive foci) were observed in all DEN+PB groups. Numbers and sizes of foci were increased even in the DEN+PB group given the lowest PB, as compared to that in the group given DEN only, while being not significant. Therefore, second experiment was done using a larger range of PB doses. Rats were given 1, 200, 300, 75, 16, 4 or 1ppm PB solutions in the same manner to the first experiment. The incidence of hepatic tumors was increased clearly in the DEN+PB groups given 300ppm PB or above, as compared to that in the group given DEN only. Linear dose-response curves for numbers and sizes of enzyme-altered hepatic foci were obtained in the dose range 16ppm-1, 200ppm PB, and numbers and/or sizes of enzyme-altered foci increased significantly in the DEN+PB groups given 300ppm PB or above. The minimum promoting dose level of PB for enzyme-altered foci, calculated from dose-response curves by the Logit model, was 15-23ppm. These results indicate that the calculated level was evident at low dose, while dose-dependence was demonstrated over a large range. The incidence of hepatic tumors, and numbers and sizes of foci decreased slightly in animals given the lowest dose (1ppm) of PB, as compared to those in animals receiving DEN only.
