Warfarin resistance is associated with a protein component of the vitamin K 2,3-epoxide reductase enzyme complex in rat liver
Warfarin resistance is associated with a protein component of the vitamin K 2,3-epoxide reductase enzyme complex in rat liver
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DOI：
10.1055/s-0037-1615151
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发表时间：
1998-07-01
影响因子：
6.7
通讯作者：
Wallin, R
中科院分区：
文献类型：
--
作者：
Cain, D;Hutson, SM;Wallin, R
华法林。世界上长期抗凝预防中使用最广泛的药物。靶向肝脏中维生素 K 循环的维生素 K 2,3-环氧化物还原酶 (VKOR)。最近，该酶已被鉴定为内质网 (ER) 膜中的多组分脂质蛋白酶系统 (17)。作为了解华法林基因耐药性的第一步，我们在本文中展示了美国饲养的正常和华法林耐药实验室大鼠品系的 VKOR 数据。金属诱导的酶复合物体外组装表明，复合物的谷胱甘肽-S-转移酶 (GST) 酶成分在 VKOR 形成后失去其 GST 活性。从华法林抗性大鼠中组装复合物后，测量到较低的 VKOR 活性。在组装复合物之前，在华法林耐药大鼠中测量 GST 活性。对华法林抑制的敏感性比正常大鼠中测量的 GST 活性低 10 倍。微粒体环氧化物水解酶 (mEH) 是 VKOR 的第二个成分。当在复合物组装之前与 VKOR 组分一起孵育时，针对 mEH 产生的抗体阻止了酶复合物的形成。对正常大鼠和华法林耐药大鼠的 mEH cDNA 进行测序显示出相同的序列。数据表明，导致华法林基因耐药的突变与 VKOR 的 GST 成分相关。
Warfarin. the most used drug in the world in long-term anticoagulation prophylaxis. targets the vitamin K 2,3-epoxide reductase (VKOR) of the vitamin K cycle in liver. Recently, the enzyme has been identified as a multicomponent lipid-protein enzyme system in the endoplasmic reticulum (ER) membrane (17). As the first step towards understanding genetic resistance to warfarin, we present in this paper data on VKOR from normal and a strain of warfarin resistant laboratory rats maintained in the United States. Metal induced in vitro assembly of the enzyme complex demonstrates that the glutathione-S-transferase (GST) enzyme component of the complex loses its GST activity upon formation of VKOR. Less VKOR activity is measured upon assembly of the complex from warfarin resistant rats. The GST activity measured in warfarin resistant rats, before assembly of the complex. is 10-fold less sensitive to warfarin inhibition than the GST activity measured in normal rats. Microsomal epoxide hydrolase (mEH) is the second component of VKOR. When incubated with the components of VKOR before assembly of the complex, antibodies raised against mEH prevented formation of the enzyme complex. Sequencing of mEH cDNAs from normal and warfarin resistant rats revealed identical sequences. The data suggest that the mutation responsible for genetic warfarin resistance is associated with the GST component of VKOR.