Pharmacodynamics of cytochrome P450 2B induction by phenobarbital, 5-ethyl-5-phenylhydantoin, and 5-ethyl-5-phenyloxazolidinedione in the male rat liver or in cultured rat hepatocytes.
Pharmacodynamics of cytochrome P450 2B induction by phenobarbital, 5-ethyl-5-phenylhydantoin, and 5-ethyl-5-phenyloxazolidinedione in the male rat liver or in cultured rat hepatocytes.
复制标题
苯巴比妥、5-乙基-5-苯基乙内酰脲和 5-乙基-5-苯基恶唑烷二酮在雄性大鼠肝脏或培养的大鼠肝细胞中诱导细胞色素 P450 2B 的药效学。
DOI：
10.1021/tx00032a008
复制
发表时间：
1993
影响因子：
4.1
通讯作者：
Lubet,RA
中科院分区：
文献类型：
--
作者：
Nims,RW;Sinclair,PR;Sinclair,JF;Thomas,PE;Jones,CR;Mellini,DW;Syi,JL;Lubet,RA
本文研究了苯巴比妥（PB）和两种结构类似物d（-5-乙基-5-苯基乙内酰脲（EPH）和d（-5-乙基-5-苯基恶唑烷二酮（EPO）诱导大鼠肝细胞色素P450 2B（P450 2B）的药效学。在F344/NCr大鼠中，通过测量免疫反应性肝P450 2B 1蛋白和通过测定睾酮的肝16/3-羟基化和（苄氧基）-和戊氧基试卤灵的O-脱烷基化来探测P450 2B的体内诱导。诱导（苄氧基）试卤灵O-脱烷基化活性也测定在成年大鼠肝细胞培养暴露于三个外源性物质。在体内研究中，通过测量血清总异生物质水平来近似估计推定活性位点的异生物质浓度，而在肝细胞培养研究中，使用培养基中的名义异生物质浓度。在体内和肝细胞培养研究中观察到P450 2B活性的浓度依赖性诱导。PB、EPH和EPO诱导P450 2B的体内ED 50值分别为-110、~ 100和~ 3000 ppm（14天给药）。PB、EPH和EPO诱导P450 2B的体内EC 50值分别为~ 9、~ 6和~ 130 mM（总血清）。在培养的大鼠肝细胞中，PB、EPH和EPO诱导（苄氧基）试卤灵O-脱烷基化活性的ED 50值分别为14.5、14.2和108 pM。这些数据表明，用肝细胞培养物获得的药效学结果代表了PB型诱导剂引起的雄性大鼠体内肝脏反应的良好定性和定量近似值。在这两种系统中，EPH和PB对P450 2B诱导的效力大致相当，而EPO的效力大致低一个数量级。
The pharmacodynamics of rat hepatic cytochromeP450 2B (P450 2B) induction by phenobarbital (PB) and two structural congeners, d (-5-ethyl-5-phenylhydantoin (EPH) and d (-5-ethyl-5-phenyloxazolidinedione (EPO), were investigated. The in vivo induction of P450 2B was probed in F344/NCr rats by measuring immunoreactive hepatic P450 2B1 protein and by assaying the hepatic 16/3-hydroxylation of testosterone and O-dealkylation of (benzyloxy)-and pentoxyresorufin. Theinduction of (benzyloxy) resorufin O-dealkylation activity was also measured in adult rat hepatocyte cultures exposed to the three xenobiotics. The concentration of xenobiotic at the putative active site in the in vivo studies was approximated by measuring serum total xenobiotic levels, whilein the hepatocyte culture studies, thenominal xenobiotic concentration in the culture medium was used. Concentration-dependent induction of P450 2B activities was observed in the in vivo and hepatocyte culture studies. Thein vivo ED50 values for P450 2B induction were—110,~ 100, and~ 3000 dietary ppm (14 days administration) for PB, EPH, and EPO, respectively. The in vivo EC50 values for P450 2B induction were~ 9,~ 6, and~ 130 mM (total serum) for PB, EPH, and EPO, respectively. In cultured rat hepatocytes, the ED50 values for induction of (benzyloxy) resorufin O-dealkylation activity were 14.5, 14.2, and 108 pM for PB, EPH, and EPO, respectively. These data indicate that pharmacodynamic results obtained with cultured hepatocytes represent a good qualitative and quantitative approximation of the in vivo hepatic responses in male rats caused by PB-type inducers. In both systems, EPH and PB were approximately equivalent in potency for P450 2B induction, while EPO was roughly an order of magnitude less potent.