Phenobarbital-inducible gene expression in developing rat liver: relationship to hepatocyte function.

The expression of phenobarbital-, pregnenolone 16 alpha-carbonitrile- and polycyclic aromatic hydrocarbon-inducible cytochromes P-450 and of phenobarbital-inducible UDP-glucuronosyltransferase was examined in developing rat liver. RNAs coding for these proteins were present in fetal rat liver and their respective concentrations remained quite stable in non-induced animals. Inducers differently affected the concentration of RNAs: clofibrate had no action, whereas methylcholanthrene was highly active in fetal liver. Induction by phenobarbital gradually increased during ontogenesis, in parallel with the augmentation of the number of hepatocyte cells in the liver. Our contribution definitively demonstrates that the ability of phenobarbital to enhance P-450 and UDPGT RNAs is strictly restricted to hepatocytes and remains roughly unchanged throughout ontogenesis. In addition, phenobarbital was also able to potentiate the inducing capacity of methylcholanthrene (i.e., raising the TCDD-binding protein) exclusively in hepatocytes. This is the first direct evidence that the number of hepatocytes in the liver, rather than a biochemical maturation, controls the expression of phenobarbital-inducible genes. Pregnenolone 16 alpha-carbonitrile was also effective as inducer in fetal and neonatal rats and its maximal effect was observed in 5-d-old neonates, suggesting a regulation mechanism temporally different from that of phenobarbital.