Lapachol inhibition of vitamin K epoxide reductase and vitamin K quinone reductase.
Lapachol inhibition of vitamin K epoxide reductase and vitamin K quinone reductase.
复制标题
拉帕胆抑制维生素 K 环氧化物还原酶和维生素 K 醌还原酶。
DOI：
10.1016/0003-9861(84)90286-8
复制
发表时间：
1984
影响因子：
3.9
通讯作者：
Suttie,JW
中科院分区：
文献类型：
--
作者：
Preusch,PC;Suttie,JW
拉帕酚[2-羟基-3-（3-甲基-2-丁烯基）-1,4-萘醌]已被证明是体外大鼠肝微粒体维生素K环氧化物还原酶和二硫苏糖醇依赖性维生素K醌还原酶的有效抑制剂。这些观察结果解释了先前在大鼠和人身上观察到的拉帕恰尔的抗凝血活性。拉帕柯对维生素K环氧化物和醌还原酶的抑制作用与香豆素抗凝抑制作用类似，在正常菌株中观察到，而在华法林耐药菌株肝微粒体中没有观察到。这种相似的作用表明，香豆素的内酯功能对其活性并不重要。拉帕醇对可溶性维生素K环氧化物还原酶的初始速度稳态抑制模式与拉帕醇与酶的氧化形式的紧密结合一致，并且对还原形式的亲和力较低。有人提出lapachhol具有类似于4-羟基香豆素的4-烯醇互变异构体结构。这些结构类似于在维生素K环氧化还原酶的化学反应机制中与酶的氧化形式结合的羟基维生素K烯酸酯中间体，从而解释了它们的高亲和力。
Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] has been shown to be a potent inhibitor of both vitamin K epoxide reductase and the dithiothreitol-dependent vitamin K quinone reductase of rat liver microsomesin vitro. These observations explain the anticoagulant activity of lapachol previously observed in both rats and humans. Lapachol inhibition of the vitamin K epoxide and quinone reductases resembled coumarin anticoagulant inhibition, and was observed in normal strain but not in warfarin-resistant strain rat liver microsomes. This similarity of action suggests that the lactone functionality of the coumarins is not critical for their activity. The initial-velocity steady-state inhibition patterns for lapachol inhibition of the solubilized vitamin K epoxide reductase were consistent with tight binding of lapachol to the oxidized form of the enzyme, and somewhat lower affinity for the reduced form. It is proposed that lapachol assumes a 4-enol tautomeric structure similar to that of the 4-hydroxy coumarins. These structures are analogs of the postulated hydroxyvitamin K enolate intermediate bound to the oxidized form of the enzyme in the chemical reaction mechanism of vitamin K epoxide reductase, thus explaining their high affinity.