证明人类CYP2C19是一个主要的奥美拉唑5-hydroxylase与重组细胞色素P450酶。

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卡拉姆反对工作组,戈尔茨坦杰,拉斯科JM Ghanayem BI

证明人类CYP2C19是一个主要的奥美拉唑5-hydroxylase与重组细胞色素P450酶。

药物金属底座Dispos。1996年10月,24 (10):1081 - 7。

PubMed ID

8894508 (在PubMed

]

文摘

奥美拉唑(OP)是一种强有力的抗溃疡的药物,它是由肝脏代谢细胞色素P450酶(P450)。然而,P450亚型的身份负责其新陈代谢一直存有争议。5-Hydroxyomeprazole (5 oh-op)形成cosegregates的多态性(S)美芬妥因4现在人类的羟基化,这是由CYP2C19。以前的体外研究表明,肝微粒体50 h-op形成与(S)美芬妥因4的羟化酶和CYP3A内容。抑制剂和CYP2C抗体研究还指出,这两种酶可能参与5-hydroxylation OP,而CYP3A似乎是主要的酶参与OP砜(OP-S)的形成。本研究评估各种CYP2C和CYP3A4酶OP的贡献人类酶代谢利用重组。CYP2C19、CYP2C8 CYP2C18, CYP2C9形成单个代谢物的液相色谱保留时间相同的5 oh-op。CYP2C19周转率为13.4 + / - 1.4 nmol /分钟/ nmol P450,而那些CYP2C8, CYP2C18, CYP2C9和2.2 + / - 0.1,1.5 + / - 0.1,约等于0.5 nmol /分钟/ nmol P450,分别。重组体人CYP3A4形成5 oh-op OP-S营业额数字为5.7 + / - 1.1和7.4 + / - 0.9 nmol /分钟/ nmol P450,分别成立了一个次要的身份不明的代谢物。CYP2C19有大幅降低5公里oh-op形成比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.

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药物酶

药物	酶	类	生物	药理作用	行动
奥美拉唑	细胞色素P450 2 c18	蛋白质	人类	未知的	底物	细节
奥美拉唑	细胞色素P450 2 c8	蛋白质	人类	未知的	底物	细节