Hildebrandt E F, Suttie J W
Biochemistry. 1982 May 11;21(10):2406-11. doi: 10.1021/bi00539a020.
The in vitro effects of two coumarin anticoagulants, warfarin and difenacoum, on rat liver microsomal vitamin K dependent carboxylase, vitamin K epoxidase, vitamin K epoxide reductase, and cytosolic vitamin K reductase (DT-diaphorase) from the livers of normal and a warfarin-resistant strain of rats have been determined. Millimolar concentrations of both coumarins are required to inhibit the carboxylase and epoxidase activities in both strains of rats. Sensitivity of DT-diaphorase to coumarin inhibition differs when a soluble or liposomal-associated substrate is used, but the diaphorases isolated from both strains of rats have comparable sensitivity. The anticoagulant difenacoum is an effective rodenticide in the warfarin-resistant strain of rats, and the only enzyme studied from warfarin-resistant rat liver that demonstrated a significant differential inhibition by the two coumarins used was the vitamin K epoxide reductase. This enzyme also showed the greatest sensitivity to coumarin inhibition among the enzymes studied. These results support the hypothesis that the physiologically important site of action of coumarin anticoagulants is the vitamin K epoxide reductase.
已测定两种香豆素抗凝剂华法林和敌鼠隆对正常大鼠及对华法林耐药大鼠肝脏微粒体维生素K依赖性羧化酶、维生素K环氧化酶、维生素K环氧化物还原酶和胞质维生素K还原酶（DT-黄递酶）的体外作用。两种香豆素均需毫摩尔浓度才能抑制两种品系大鼠的羧化酶和环氧化酶活性。当使用可溶性或脂质体相关底物时，DT-黄递酶对香豆素抑制的敏感性有所不同，但从两种品系大鼠中分离出的黄递酶具有相当的敏感性。抗凝剂敌鼠隆在对华法林耐药的大鼠品系中是一种有效的灭鼠剂，在对华法林耐药大鼠肝脏中研究的唯一一种对所使用的两种香豆素表现出显著差异抑制作用的酶是维生素K环氧化物还原酶。在所研究的酶中，这种酶对香豆素抑制也表现出最大的敏感性。这些结果支持了香豆素抗凝剂生理上重要的作用位点是维生素K环氧化物还原酶这一假说。
