Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes.
Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes.
复制标题
使用奎尼丁抑制作用来确定金雀花碱/德布异喹细胞色素 P450 在人肝微粒体美托洛尔氧化中的作用。
DOI：
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发表时间：
1988
影响因子：
3.5
通讯作者：
H. Woods
中科院分区：
文献类型：
--
作者：
S. Otton;H. Crewe;M. Lennard;G. Tucker;H. Woods
The oxidation of the beta adrenoceptor antagonist metoprolol exhibits genetic polymorphism of the sparteine/debrisoquine (SP/DB) type. The alpha-hydroxylation of metoprolol is absent in poor metabolizers, whereas metoprolol O-demethylation is only partially impaired, suggesting that an enzyme or enzymes other than cytochrome P450-SP/DB contribute to the latter reaction. Using inhibition by the quinidine/quinine isomer pair as a marker for the activity of cytochrome P450-SP/DB, the role of this enzyme in the in vitro oxidation of the enantiomers of metoprolol by human liver microsomes was examined. Unlike alpha-hydroxylation, only a portion of metoprolol O-demethylation showed the stereoselective inhibition by quinidine and quinine characteristic of in vitro reactions catalyzed by cytochrome P450-SP/DB. Furthermore, the kinetics of metoprolol O-demethylation were biphasic, the two components of O-demethylase activity being distinguishable by their enantioselectivity and sensitivity to inhibition by quinidine. Microsomes from one liver formed no detectable alpha-hydroxymetoprolol, and O-demethylation by these microsomes corresponded to the low affinity site observed in eight other livers. The rate of metoprolol O-demethylation by the quinidine-inhibitable high affinity component was directly proportional to the rate of alpha-hydroxylation. These findings support the hypothesis that cytochrome P450-SP/DB catalyzes the formation of alpha-hydroxymetoprolol, but is only partially responsible for metoprolol O-demethylation. Such a mechanism could explain the previously reported inability to detect polymorphism in the O-demethylation pathway in vivo.
