维生素k2,3 -环氧还原酶:4-羟基香豆素抗凝血活性立体选择性的基础。
文章的细节
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引用
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Thijssen HH, Baars LG, Vervoort-Peters HT
维生素k2,3 -环氧还原酶:4-羟基香豆素抗凝血活性立体选择性的基础。
中华药物学杂志1988 11月;95(3):675-82。
- PubMed ID
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3207986 (PubMed视图]
- 摘要
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1.对48小时前预负荷了示踪剂剂量(6微克)的14c标记的R-或s -华法林的大鼠给予s -华法林(1 mg kg-1静脉注射),可导致这些化合物的血浆水平升高。这是由于微粒体(维生素K 2,3-环氧化物(K0)还原酶)结合的R-或S-[14C]-华法林被未标记的4-羟基香豆素所取代。复发率R-组比s -华法林组高3-4倍;释药T1/2:分别为1.2 +/- 0.04和3.7 +/- 0.6 h。2.由R-或S-[14C]-华法林预处理的大鼠制备的肝微粒体,仅在二硫苏糖醇存在时才释放这些化合物(DTT;10毫米)。R-的释放速率高于s -华法林处理的微粒体。3. 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.
引用本文的药物库数据
- 药物靶点
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药物 目标 种类 生物 药理作用 行动 Phenprocoumon 维生素K环氧还原酶复合亚基1 蛋白质 人类 是的抑制剂细节