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.
Kurata
N
N
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Yoshida
T
T
Kuroiwa
Y
Y
Masuko
T
T
Hashimoto
Y
Y
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000378:metabolism; D000633:Aminopyrine N-Demethylase / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing); D000633:Aminopyrine N-Demethylase; D000624:5-Aminolevulinate Synthetase; D010634:Phenobarbital