Kurata N, Yoshida T, Kuroiwa Y, Masuko T, Hashimoto Y
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Res Commun Chem Pathol Pharmacol. 1989 Aug;65(2):161-79.
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.
通过采用两种不同的给药方案，研究苯巴比妥对参与药物和血红素代谢的大鼠肝酶变化的长期影响，这两种给药方案会产生对该药物的耐受性（耐受组）和/或依赖性（依赖组）。在两个治疗组中，苯巴比妥均显著且持续地诱导细胞色素P - 450和氨基比林N - 脱甲基酶；在早期，耐受组的反应比依赖组更强。此后，药物代谢酶的诱导程度逐渐降低，最终维持在相应对照水平的两倍。同样，细胞色素P - 450b + e含量（主要的苯巴比妥诱导型之一）的诱导维持在细胞色素P - 450总含量的40%。苯巴比妥治疗导致δ-氨基乙酰丙酸合成酶（ALAS）活性增加，血红素加氧酶（HO）活性降低。这些参与血红素代谢的酶的变化与药物代谢酶的变化一致。最后，在终止苯巴比妥治疗后测定酶含量和活性的变化，并使用蛋白质合成抑制剂计算酶的生物学半衰期。终止苯巴比妥治疗后，两组之间细胞色素P - 450和细胞色素P - 450b + e含量的变化未观察到显著差异。然而，停药后两组之间ALAS和HO活性的变化存在显著差异；依赖组的变化与血清苯巴比妥水平的降低相对应。另一方面，微粒体药物代谢酶的生物学半衰期在耐受组中比在依赖组中更长。
