Consequences of the Y139F Vkorc1 mutation on resistance to AVKs: in-vivo investigation in a 7th generation of congenic Y139F strain of rats.
Consequences of the Y139F Vkorc1 mutation on resistance to AVKs: in-vivo investigation in a 7th generation of congenic Y139F strain of rats.
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DOI：
10.1097/fpc.0b013e32832ee55b
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发表时间：
2009-10
影响因子：
2.6
通讯作者：
Benoit E
中科院分区：
文献类型：
--
作者：
Grandemange A;Kohn MH;Lasseur R;Longin-Sauvageon C;Berny P;Benoit E
在人类中，华法林用作抗凝剂，以降低血栓栓塞临床事件的风险。在害虫防治中，Warcantine衍生物也用作杀鼠剂。编码抗凝剂靶向蛋白的基因是维生素K-2，3-环氧化物还原酶亚基1（VKORC 1）。自2004年发现以来，已经在需要极端抗维生素K剂量的患者或难以用抗凝血灭鼠剂控制的啮齿动物野生种群中确定了各种氨基酸和转录调节改变VKORC 1突变。一个尚未解决的问题涉及VKORC 1对人类和啮齿动物遗传背景的依赖性，这些人和啮齿动物对抗凝剂反应微弱或根本没有反应。此外，需要进一步分析的一个重要问题是Vkorc 1基因在介导对最近开发的华法林衍生物（superwarfarins）的耐药性中的作用。在这项研究中，我们通过使用野生捕获的抗凝血剂抗性大鼠作为供体，将Vkorc 1中第139位的Y > F氨基酸改变引入到抗凝血剂敏感的Sprague-Dawley受体品系的遗传背景中，来培育准遗传大鼠品系。在这篇手稿中，我们报告了凝血酶原时间测量的F7代暴露后，氯敌鼠，溴敌隆，敌鼠灵和difethialone。我们观察到，突变Y139 F介导的阻力，否则敏感的遗传背景时，暴露于氯敌和溴敌隆。然而，超级warfarins，difenacoum和difethialone的生理反应，可能是强烈依赖于其他基因位于同源区间（28.3 cM）外的括号Vkorc 1在我们的F7代同源株。
In humans, warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events. Warfarin derivatives are also used as rodenticides in pest control. The gene encoding the protein targeted by anticoagulants is the Vitamin K-2,3-epoxide reductase subunit 1 (VKORC1). Since its discovery in 2004, various amino acid and transcription-regulatory altering VKORC1 mutations have been identified in patients who required extreme antivitamin K dosages, or wild populations of rodents that were difficult to control with anticoagulant rodenticides. One unresolved question concerns the dependency of the VKORC1 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants. Moreover, an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives (superwarfarins). In this study, we bred a quasicongenic rat strain by using a wild-caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque–Dawley recipient strain. In this manuscript we report the prothrombin times measured in the F7 generation after exposure to chlorophacinone, bromadiolone, difenacoum and difethialone. We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone. However, the physiological response to the super-warfarins, difenacoum and difethialone, may be strongly dependent on other genes located outside the congenic interval (28.3 cM) bracketing the Vkorc1 in our F7 generation congenic strain.