HYDROXYLATION OF WARFARIN BY HUMAN CDNA-EXPRESSED CYTOCHROME-P-450 - A ROLE FOR P-4502C9 IN THE ETIOLOGY OF (S)-WARFARIN DRUG-INTERACTIONS
HYDROXYLATION OF WARFARIN BY HUMAN CDNA-EXPRESSED CYTOCHROME-P-450 - A ROLE FOR P-4502C9 IN THE ETIOLOGY OF (S)-WARFARIN DRUG-INTERACTIONS
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DOI：
10.1021/tx00025a009
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发表时间：
1992-01-01
影响因子：
4.1
通讯作者：
TRAGER, WF
中科院分区：
文献类型：
--
作者：
RETTIE, AE;KORZEKWA, KR;TRAGER, WF
先前的动力学研究已经确定了存在于人肝微粒体中的高亲和力（S）-华法林7-羟化酶，其似乎负责终止华法林的生物活性。 已知抑制（S）-7-羟基华法林（人体内外消旋华法林的非活性主要代谢产物）的形成是华法林与其他治疗药物联合给药后临床上发生的几种药物相互作用的原因。 为了鉴定参与这种特定毒性的人肝细胞色素P-450的特定形式，我们测定了HepG 2细胞中表达的11种人细胞色素P-450形式对（R）-和（S）-华法林的代谢特征。 在检查的11种形式中，仅2C 9显示出适合于高亲和力人肝微粒体（S）-7-羟化酶的区域选择性和立体选择性。 我们进一步比较了Michaelis-Menten和磺胺苯吡唑对cDNA表达的2C 9和人肝微粒体催化的（S）-华法林7-羟基化的抑制常数。 获得了类似的动力学常数为每种酶源。 它的结论是，2C 9很可能是一个主要形式的人肝P-450调节体内抗凝活性的药物。 进一步得出结论，由于生物学上更有效的S-对映异构体清除率降低而引起的与华法林的药物相互作用可能以抑制P-450 2C 9为共同基础。
Previous kinetic studies have identified a high-affinity (S)-warfarin 7-hydroxylase present in human liver microsomes which appears to be responsible for the termination of warfarin's biological activity. Inhibition of the formation of (S)-7-hydroxywarfarin, the inactive, major metabolite of racemic warfarin in humans, is known to be the cause of several of the drug interactions experienced clinically upon coadministration of warfarin with other therapeutic agents. In order to identify the specific form(s) of human liver cytochrome P-450 involved in this particular toxicity, we have determined the metabolic profiles of 11 human cytochrome P-450 forms expressed in HepG2 cells toward both (R)- and (S)-warfarin. Of the 11 forms examined only 2C9 displayed the regioselectivity and stereoselectivity appropriate for the high-affinity human liver microsomal (S)-7-hydroxylase. We further compared Michaelis-Menten and sulfaphenazole inhibition constants for (S)-warfarin 7-hydroxylation catalyzed by cDNA-expressed 2C9 and by human liver microsomes. Similar kinetic constants were obtained for each enzyme source. It is concluded that 2C9 is likely to be a principal form of human liver P-450 which modulates the in vivo anticoagulant activity of the drug. It is further concluded that those drug interactions with warfarin that arise as a result of decreased clearance of the biologically more potent S-enantiomer may have as their common basis the inhibition of P-450 2C9.