人CYP2C19是一种主要的奥美拉唑5-羟化酶，如重组细胞色素P450酶所示。

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Karam WG, Goldstein JA, Lasker JM, Ghanayem BI

人CYP2C19是一种主要的奥美拉唑5-羟化酶，如重组细胞色素P450酶所示。

《药物代谢处置》1996年10月;24(10):1081-7。

PubMed ID

8894508 (PubMed视图

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摘要

奥美拉唑(OP)是一种由肝脏细胞色素P450 (P450)酶代谢的抗溃疡药物。然而，负责其代谢的P450亚型的身份一直存在争议。5-羟基奥美拉唑(5OH-OP)的形成与人类(S)-mephenytoin 4’-羟基化多态性共分离，目前已知该多态性由CYP2C19介导。前期体外研究表明，肝微粒体50H-OP的形成与(S)-甲苯妥因4’-羟化酶和CYP3A含量相关。抑制剂和CYP2C抗体研究也表明，这两种酶都可能参与OP的5-羟基化，而CYP3A似乎是参与OP砜(OP- s)形成的主要酶。本研究利用重组人酶评估了各种CYP2C和CYP3A4酶对OP代谢的贡献。CYP2C19、CYP2C8、CYP2C18、CYP2C9形成单一代谢物，其HPLC保留时间与5OH-OP相同。CYP2C19的P450的翻转数为13.4 +/- 1.4 nmol/min/nmol，而CYP2C8、CYP2C18和CYP2C9的P450的翻转数分别为2.2 +/- 0.1、1.5 +/- 0.1和约等于0.5 nmol/min/nmol。重组人CYP3A4形成P450的周转数分别为5.7 +/- 1.1和7.4 +/- 0.9 nmol/min/nmol的5OH-OP和OP-S，形成一种次要的未鉴定代谢产物。CYP2C19的5OH-OP形成KM明显低于CYP3A4、CYP2C8或CYP2C18。 Antibody to CYP2C proteins inhibited approximately equal to 70% of OP 5-hydroxylation at low substrate concentrations, comparable to those that may be encountered at therapeutically relevant doses, whereas antibody to CYP3A4 inhibited approximately equal to 30% of the activity. At high substrate concentrations, the contributions of the two enzymes to OP hydroxylation were roughly comparable (40-50%). In contrast, OP-S formation was completely inhibited by antibody to CYP3A4 proteins. The present study provides the first direct confirmation, using human recombinant P450 enzymes and selective antibody inhibition, that CYP2C19 is a major high affinity OP 5-hydroxylase and CYP3A4 is a low affinity OP-hydroxylating enzyme. The current work also shows, for the first time, that other CYP2C enzymes (CYP2C8, CYP2C9, and CYP2C18) may contribute to OP hydroxylation at high substrate concentrations. In contrast, OP-S was formed principally by CYP3A4.

引用本文的药物库数据

药物酶

药物	酶	种类	生物	药理作用	行动
奥美拉唑	细胞色素P450 2C18	蛋白质	人类	未知的	底物	细节
奥美拉唑	细胞色素P450 2C8	蛋白质	人类	未知的	底物	细节