Long-term effects of phenobarbital on rat liver microsomal drug-metabolizing enzymes and heme-metabolizing enzyme.

Long-term effects of phenobarbital on changes of rat hepatic enzymes involved in drug and heme metabolism were examined by employing two different treatment schedules which produce tolerance (tolerant group) and/or dependence (dependent group) against the drug. In both treatment groups, phenobarbital produced a marked and persistent induction of cytochrome P-450 and aminopyrine N-demethylase; the response was greater in the tolerant group than that in the dependent group at the early time periods. Thereafter, the magnitude of the induction of drug-metabolizing enzymes gradually decreased and finally was maintained at two-fold of the corresponding control levels. Likewise, the induction of cytochrome P-450b+e content, one of the major phenobarbital inducible species, was maintained at 40% of the total cytochrome P-450 content. Phenobarbital treatment resulted in increase of delta-aminolevulinate synthetase (ALAS) activity and a decrease in heme oxygenase (HO) activity. Changes of these enzymes involved in heme metabolism coincided with changes of the drug-metabolizing enzymes. Finally, the changes of enzyme content and activity after terminating phenobarbital treatment were determined and enzyme biological half-lives were calculated employing protein synthesis inhibitors. No significant differences in the changes of cytochrome P-450 and cytochrome P-450b+e content between the groups were observed after terminating phenobarbital treatment. However, changes of ALAS and HO activities after terminating the drug were significantly different between the groups; changes in the dependent group corresponded to the decrease in serum phenobarbital levels. On the other hand, biological half-lives of microsomal drug-metabolizing enzymes were longer in the tolerant group than in the dependent group.