Higher body and carcass (body - liver) weights in
sodium phenobarbital (PB) treated mice correlate with formation of multiple
hepatocellular adenomas in yellow Avy/A and agouti A/a (C3H x VY) F1 hybrid male mice. To assess differences in PB induction of hepatic
drug metabolizing
enzymes, yellow Avy/A (C3H x VY) F1 hybrid male mice were fed 0.05%
sodium PB in NIH-31 diet for 7 months. Livers from the heaviest and lightest mice in the untreated and PB groups were assayed. Total
cytochrome P450 content,
cytochrome P450IA-selective 7-ethoxyresorufin-O-deethylase and P450IIIA-selective testosterone-6 beta-
hydroxylase activities were preferentially induced in the light mice. In contrast, P450IIB-selective 7-pentoxyresorufin-O-dealkylase activity was increased only 3-fold by PB in the light mice but 6-fold in the heavy mice.
Testosterone UDP-
glucuronyltransferase and gamma-glutamyltranspeptidase activities were induced in the light mice but not in the heavy mice.
Glutathione-S-transferase N1:1-dependent activity was induced preferentially in the heavy mice. Significant differences also occurred in constitutive expression of P450IIIA-selective testosterone-6 beta-
hydroxylase, P450IA-selective 7-ethoxyresorufin-O-deethylase and
testosterone UDP-
glucuronyltransferase activities between the untreated weight groups. Thus, expression of constitutive and PB-inducible forms of hepatic
drug metabolizing
enzymes differs between heavy and light Avy/A (C3H x VY) F1 hybrid subpopulations. This suggests that differential susceptibility to PB promotion of
hepatocellular adenomas among genetically identical mice is accompanied by differences in the regulation of gene expression.