Dayer P, Kronbach T, Eichelbaum M, Meyer U A
Department of Pharmacology, University of Basel, Switzerland.
Biochem Pharmacol. 1987 Dec 1;36(23):4145-52. doi: 10.1016/0006-2952(87)90573-9.
The genetically controlled polymorphic oxidation of debrisoquine and sparteine is caused by the absence or functional deficiency of a cytochrome P-450 isozyme. In order to elucidate the mechanisms underlying the differences in cytochrome P-450 function we have studied the 1'-hydroxylation of the prototype drug bufuralol in human liver microsomes of individuals phenotyped in vivo as extensive metabolizers (EM, N = 10), poor metabolizers (PM, N = 5) and in subjects with an intermediate rate of metabolism (IM, N = 4). PM- as compared to EM-microsomes were characterized by a decreased Vmax for (+)-bufuralol 1'-hydroxylation (7.51 +/- 2.03 nmol X mg-1 X hr-1 vs 11.95 +/- 4.80 nmol X mg-1 X hr-1) but not for (-)-bufuralol 1'-hydroxylation (4.72 +/- 0.87 nmol X mg-1 X hr-1 vs 5.55 +/- 1.49 nmol X mg-1 X hr-1). The apparent Km for (+)-bufuralol 1'-hydroxylation was increased in PM microsomes (118 +/- 84.9 microM vs 17.9 +/- 6.30 microM). Inhibition of bufuralol 1'-hydroxylation by quinidine was biphasic in EM microsomes, providing further support for the involvement of at least two cytochrome P-450 isozymes. Quinidine acted as a competitive inhibitor of only the high affinity/stereoselectivity component of the reaction. Our data suggest that the debrisoquine/sparteine type of oxidation polymorphism is caused by an almost complete loss of a minor cytochrome P-450 isozyme which has a high affinity and stereoselectivity for (+)-bufuralol and a high sensitivity to inhibition by quinidine.
去甲丙咪嗪和司巴丁的基因控制多态性氧化是由一种细胞色素P - 450同工酶的缺失或功能缺陷引起的。为了阐明细胞色素P - 450功能差异背后的机制，我们研究了原型药物布呋洛尔在体内表型为快代谢者（EM，N = 10）、慢代谢者（PM，N = 5）和代谢速率中等者（IM，N = 4）的人肝微粒体中的1'-羟基化作用。与EM微粒体相比，PM微粒体中（+）-布呋洛尔1'-羟基化的Vmax降低（7.51±2.03 nmol·mg-1·hr-1对11.95±4.80 nmol·mg-1·hr-1），但（-）-布呋洛尔1'-羟基化的Vmax没有降低（4.72±0.87 nmol·mg-1·hr-1对5.55±1.49 nmol·mg-1·hr-1）。PM微粒体中（+）-布呋洛尔1'-羟基化的表观Km增加（118±84.9 μM对17.9±6.30 μM）。奎尼丁对布呋洛尔1'-羟基化的抑制在EM微粒体中呈双相性，这为至少两种细胞色素P - 450同工酶的参与提供了进一步支持。奎尼丁仅作为反应的高亲和力/立体选择性成分的竞争性抑制剂。我们的数据表明，去甲丙咪嗪/司巴丁类型的氧化多态性是由一种次要的细胞色素P - 450同工酶几乎完全丧失引起的，该同工酶对（+）-布呋洛尔具有高亲和力和立体选择性，并且对奎尼丁抑制高度敏感。
