维生素K 2, 3-epoxide还原酶:立体选择性4-hydroxycoumarin抗凝活动的基础。

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Thijssen HH,巴尔LG、Vervoort-Peters HT

维生素K 2, 3-epoxide还原酶:立体选择性4-hydroxycoumarin抗凝活动的基础。

Br J杂志。1988年11月,95 (3):675 - 82。

PubMed ID

3207986 (在PubMed

]

文摘

1。S-warfarin管理(1毫克公斤增长值)大鼠前预装48 h与示踪剂(6微克)14 c-labelled R -或S-warfarin这些化合物的离子水平增加引起的。这是由于微粒体的置换(维生素K 2, 3-epoxide (K0)还原酶)结合R -或S - [14 c]华法林的未标记的4-hydroxycoumarin管理。再现率高出3 - 4倍R -比S-warfarin;t1/2版本:1.2 + / - 0.04和3.7 + / - 0.6 h,分别。2。从大鼠肝微粒体准备使用R -和S - [14 c]华法林,公布这些化合物只有在二硫苏糖醇(DTT;10毫米)。释放的速率是R -高于S-warfarin-treated微粒体。3所示。 Liver microsomes treated in vitro with R- or S-acenocoumarol could be reactivated by DTT (10 mM). Reactivation was higher for the R- than for the S-acenocoumarol-treated microsomes. 4. The microsomal vitamin K0 reductase activity under 'normal' assay conditions ([DTT] = 2 mM) was as sensitive for R- as for S-4-hydroxycoumarins. At elevated DTT concentrations (= 42 mM) the rate of vitamin K0 conversion was about 1.5 fold higher in the presence of the R-isomers than in the presence of the S-isomers. For instance, at 2 mM DDT the reductase activities in the presence of 2.6 microM R- and S-warfarin were about 15% of control. At 42 mM DTT the activities were 90 and 65% of control, respectively. 5. In the in vitro experiments acenocoumarol appeared to be more potent than warfarin and phenprocoumon. 6. The following mechanism is proposed: vitamin K0 reductase becomes oxidized during substrate reduction. The oxidized (i.e. inactive) form binds equally to the R- and S-enantiomers of 4- hydroxycoumarins. The attached (covalently bound?) coumarin is released by the reactivation (i.e. reduction) of the enzyme. However, the rate of reactivation is strongly attenuated by the attached coumarin. This effect is more pronounced for the S-configuration of the 4-hydroxycoumarin anticoagulants.

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药物靶点

药物	目标	类	生物	药理作用	行动
Phenprocoumon	复合维生素K环氧还原酶亚基1	蛋白质	人类	是的	抑制剂	细节