Normal and warfarin-resistant rat hepatocyte metabolism of vitamin K 2,3-epoxide: evidence for multiple pathways of hydroxyvitamin K formation.
Normal and warfarin-resistant rat hepatocyte metabolism of vitamin K 2,3-epoxide: evidence for multiple pathways of hydroxyvitamin K formation.
复制标题
正常和华法林耐药大鼠肝细胞维生素 K 2,3-环氧化物代谢：羟基维生素 K 形成多种途径的证据。
DOI：
10.1016/0003-9861(88)90571-1
复制
发表时间：
1988
影响因子：
3.9
通讯作者：
Fasco,MJ
中科院分区：
文献类型：
--
作者：
Trivedi,LS;Rhee,M;Galivan,JH;Fasco,MJ
维生素K和3-（和/或2）-羟基-2，3-二氢-2-甲基-3-植基-1，4-萘醌（羟基维生素K）已被确定为维生素K 2，3-环氧化物与正常和华法林耐药大鼠肝细胞孵育的代谢产物。加入到细胞外介质中的二硫苏糖醇差异增强了两种代谢产物的形成：羟基维生素K的形成，几乎检测不到的情况下，二硫苏糖醇，特别受到影响。向正常大鼠肝细胞培养物中加入维生素K 2，3-环氧化物还原酶抑制剂华法林（5至100 μm）和大隆（1至5 μm），可使羟维生素K形成略有增加，并显著抑制维生素K的形成。在较高浓度下，大隆是羟基维生素K形成的弱抑制剂。与正常大鼠肝细胞相比，华法林耐药大鼠肝细胞催化羟维生素K形成的速度快1.5至2倍，维生素K形成的速度慢1.5至2倍。向这些培养物中加入华法林对环氧化物代谢为羟基维生素K没有影响，仅部分减少代谢为维生素K。相比之下，大隆（1 μm）的加入产生50%的抑制羟基维生素K的形成和几乎完全抑制维生素K的形成。这些数据表明，在抗性，但不是在正常大鼠肝细胞，维生素K 2，3-环氧化物还原酶作出了显着的贡献，羟维生素K的形成。存在于两种菌株中的第二种巯基依赖性途径也参与该代谢物的形成。他们还表明，在耐药大鼠中，华法林对维生素K 2，3-环氧化物还原酶的抑制作用，以及推测的巯基依赖性维生素K还原酶的抑制作用是不完全的，并且与浓度无关。
Vitamin K and 3- (and/or 2)-hydroxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone (hydroxyvitamin K) have been identified as metabolites of vitamin K 2,3-epoxide incubated with hepatocytes isolated from normal and warfarin-resistant rats. Dithiothreitol added to the extracellular medium differentially enhanced the formation of both metabolites: hydroxyvitamin K formation, almost undetectable in the absence of dithiothreitol, was particularly affected. Addition of the vitamin K 2,3-epoxide reductase inhibitors warfarin (5 to 100 μm) and brodifacoum (1 to 5 μm) to normal rat hepatocyte cultures produced a slight increase in hydroxyvitamin K formation and a marked inhibition of vitamin K formation. Brodifacoum was a weak inhibitor of hydroxyvitamin K formation at higher concentrations. Hepatocytes from warfarin-resistant rats catalyzed hydroxyvitamin K formation 1.5 to 2 times faster and vitamin K formation 1.5 to 2 times slower than did normal rat hepatocytes. The addition of warfarin to these cultures had no effect on epoxide metabolism to hydroxyvitamin K and only partially diminished metabolism to vitamin K. In contrast, brodifacoum (1 μm) addition produced 50% inhibition of hydroxyvitamin K formation and almost complete inhibition of vitamin K formation. These data suggest that in resistant, but not in normal rat hepatocytes, the vitamin K 2,3-epoxide reductase makes a significant contribution to hydroxyvitamin K formation. A second sulfhydryl-dependent pathway, present in both strains, is also involved in the formation of this metabolite. They also suggest that in resistant rats, warfarin inhibition of the vitamin K 2,3-epoxide reductase, and presumably the sulfhydryl-dependent vitamin K reductase, is incomplete and independent of concentration.