WARFARIN INHIBITION OF VITAMIN-K 2,3-EPOXIDE REDUCTASE IN RAT-LIVER MICROSOMES
WARFARIN INHIBITION OF VITAMIN-K 2,3-EPOXIDE REDUCTASE IN RAT-LIVER MICROSOMES
复制标题
DOI：
10.1021/bi00293a031
复制
发表时间：
1983-01-01
期刊：
影响因子：
2.9
通讯作者：
FRIEDMAN, PA
中科院分区：
文献类型：
--
作者：
FASCO, MJ;PRINCIPE, LM;FRIEDMAN, PA
Warcantine是一种在体外和体内有效的维生素K 2，3-环氧化物还原为维生素K的抑制剂。二硫苏糖醇是维生素K 2，3-环氧化物还原酶的体外还原剂，可通过尚未确定的机制拮抗Warcantine对还原酶的抑制。用大鼠肝微粒体进行实验，以表征维生素K 2，3-环氧化物、华法林和二硫苏糖醇之间存在的相互作用。增加浓度的二硫苏糖醇减少抑制还原酶华法林。当二硫苏糖醇存在于还原酶暴露于华法林之前时，其抑制作用低于暴露于华法林后存在相同浓度的二硫苏糖醇时的抑制作用。当二硫苏糖醇最初存在时，华法林对还原酶的最大抑制作用以慢得多的速率发生。当底物浓度为100 μ M维生素K2，3-环氧化物时，华法林对还原酶的抑制作用大于当底物浓度为10 μ M环氧化物时。显然，二硫苏糖醇直接或间接还原还原酶内的关键二硫化物，该二硫化物在环氧化物底物还原期间被再氧化，华法林和维生素K 2，3-环氧化物彼此之间不存在竞争性，华法林结合（产生抑制作用）仅发生在还原酶的二硫化物形式上。一旦结合，华法林抑制二硫苏糖醇对关键二硫化物的进一步还原。因此，二硫苏糖醇通过维持还原酶处于还原状态来拮抗华法林。
Warfarin is a potent inhibitor of vitamin K 2,3-epoxide reduction to vitamin K in vitro and in vivo. Dithiothreitol, an in vitro reductant for the vitamin K 2,3-epoxide reductase, antagonizes inhibition of the reductase by Warfarin via mechanisms that have not been determined. Experiments with rat hepatic microsomes were undertaken to characterize the interactions that exist between vitamin K 2,3-epoxide, warfarin and dithiothreitol. Increasing concentrations of dithiothreitol decreased inhibition of the reductase by warfarin. When dithiothreitol was present prior to exposure of the reductase to warfarin, there was less inhibition than when the same concentration of dithiothreitol was present after its exposure to warfarin. Maximum inhibition of the reductase by warfarin occurred at a much slower rate when dithiothreitol was present initially. Inhibition of the reductase by warfarin was greater when the substrate concentration was 100 .mu.M vitamin K 2,3-epoxide than when it was 10 .mu.M epoxide. Evidently, dithiothreitol reduces either directly or indirectly a critical disulfide within the reductase that is reoxidized during reduction of the epoxide substrate, warfarin and vitamin K 2,3-epoxide are not competitive with respect to one another and warfarin binding, which produces inhibition, occurs solely to the disulfide form of the reductase. Once it is bound, warfarin inhibits further reduction of the critical disulfide by dithiothreitol. Dithiothreitol therefore antagonizes warfarin by maintaining the reductase in the reduced state.