Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats.
Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats.
复制标题
大鼠重复给予丙咪嗪后细胞色素 P450 同工酶的抑制和诱导。
DOI：
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发表时间：
1995
影响因子：
3.9
通讯作者：
S. Narimatsu
中科院分区：
文献类型：
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作者：
Y. Masubuchi;C. Takahashii;N. Fujio;T. Horie;T. Suzuki;S. Imaoka;Y. Funae;S. Narimatsu
反复口服丙咪嗪（100 mg/kg/天，连续5天）导致大鼠肝微粒体碎片喹4-羟化酶活性下降，这是一种由细胞色素P450 (CYP) 2D1催化的特征性反应。其他cyp2d依赖性反应（如布尼特洛尔4-羟基化、利多卡因3-羟基化和心得安4-、5-和7-羟基化）也受到了影响，但其他CYP同功酶催化的反应没有受到影响。丙咪嗪预处理未改变免疫化学测定的CYP2D蛋白含量，提示CYP2D失活。丙咪嗪预处理还导致总CYP含量增加，并在454nm处形成了铁基CYP代谢中间体（MI）复合物吸收。虽然用铁氰化物处理这些微粒体以解离mi -复合物，增加了CYP的总含量，但CYP2D依赖的活性没有恢复，这表明mi -复合物不是CYP2D抑制的主要原因。该预处理方案导致免疫化学测定的CYP2A1、CYP2B1、CYP2B2、CYP2C6和CYP3A2水平显著升高，睾酮的2 α -、2 β -、6 β -、7 α -、16 α -和16 β -羟基化和17-氧化活性显著升高。这些结果表明丙咪嗪对肝脏CYP系统有两种作用（即作为CYP2D酶的抑制剂和作为苯巴比妥型诱导剂）。
Repetitive oral administration of imipramine (100 mg/kg/day for 5 days) caused a decrease in rat liver microsomal debrisoquine 4-hydroxylase activity, a characteristic reaction catalyzed by cytochrome P450 (CYP) 2D1. Other CYP2D-dependent reactions (such as bunitrolol 4-hydroxylation, lidocaine 3-hydroxylation, and propranolol 4-, 5- and 7-hydroxylations) were also impaired by the treatment, but not those catalyzed by other CYP isozymes. Imipramine pretreatment did not change the immunochemically determined content of the CYP2D protein, suggesting that CYP2D is inactivated. Imipramine pretreatment also resulted in an increase in total CYP content and in formation of a ferrous CYP metabolic intermediate (MI)-complex absorbing at 454 nm. Although the total CYP content was increased by the treatment of these microsomes with ferricyanide to dissociate the MI-complex, the CYP2D-dependent activities were not restored, suggesting that the MI-complex was not the primary cause of CYP2D inhibition. This pretreatment regimen caused marked increases in immunochemically determined levels of CYP2A1, CYP2B1, CYP2B2, CYP2C6, and CYP3A2, and in the activities of 2 alpha-, 2 beta-, 6 beta-, 7 alpha-, 16 alpha-, and 16 beta-hydroxylation and 17-oxidation of testosterone. These results indicate that imipramine has two actions on the liver CYP system (i.e. as an inhibitor of the CYP2D enzyme and as a phenobarbital-type inducer).