The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan
The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan
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DOI：
10.1016/j.pestbp.2012.04.011
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发表时间：
2012-06-01
影响因子：
4.7
通讯作者：
Ishizuka, Mayumi
中科院分区：
文献类型：
--
作者：
Tanaka, Kazuyuki D.;Kawai, Yusuke K.;Ishizuka, Mayumi
华法林在世界范围内被广泛用作灭鼠剂。它通过抑制维生素k2,3 -环氧化物还原酶（VKOR）活性来抑制血液凝固，从而导致出血。然而，据报道，反复或长期使用华法林会导致野生啮齿动物出现耐药性。这种抗性可以解释为什么在日本许多地区难以控制啮齿动物。在本报告中，我们研究了VKOR基因的突变（包括VKOR复合物亚基1 (VKORC1)），同时分析了黑鼠（Rattus Rattus）的VKOR和凝血因子活性，以便更好地了解该物种的华法林耐药机制。我们对生活在日本野外的275只老鼠的VKORC1基因进行了测序。我们发现了几种新型碱基取代，其中一些使华法林耐药。生理条件下华法林敏感大鼠与华法林耐药大鼠凝血时间无差异。然而，在华法林给药后，华法林耐药大鼠没有发现任何影响，尽管华法林敏感大鼠的凝血时间延长。我们还测定了华法林耐药和华法林敏感大鼠肝微粒体vkor依赖性活性的动力学差异。华法林耐药大鼠的VmaxIK值比敏感大鼠低2-3倍。此外，我们报告了在东京地区发现的抗性大鼠的VKOR活性被华法林抑制得很差。最后，我们得出结论，日本黑鼠的VKOR活性降低和华法林耐药性可能是由于VKORC1基因突变所致。然而，需要进一步的研究来阐明这些大鼠如何能够维持足够的维生素k依赖性凝血因子水平，同时表现出低VKOR活性和华法林抗性。(C) 2012爱思唯尔公司版权所有。
Warfarin is commonly used worldwide as a rodenticide. It inhibits blood coagulation by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity leading to hemorrhage. However, it has been reported that repeated or long-term treatment with warfarin results in resistance emerging in wild rodents. Such resistance may explain why it is difficult to control rodents in many regions in Japan. In this report, we studied mutations in the VKOR gene (including the VKOR complex subunit 1 (VKORC1)), while also analyzing VKOR and clotting factor activity in black rats (Rattus rattus) in order to understand better the mechanism of warfarin resistance in this species.We sequenced the VKORC1 gene from 275 rats living in the wild in Japan. We found several types of novel base substitutions, some of which conferred warfarin resistance.There was no difference in coagulation times between warfarin-sensitive and resistant rats measured under physiological conditions. However, after warfarin administration, no effect was noted in warfarinresistant rats, although a prolonged coagulation time was noted in warfarin-sensitive rats.We also determined the kinetic differences in hepatic microsomal VKOR-dependent activity between warfarin-resistant and sensitive rats. Warfarin-resistant rats showed 2-3-fold lower VmaxIK values than did sensitive rats. In addition, we report that resistant rats found in the Tokyo area had a VKOR activity which was poorly inhibited by warfarin.Finally, we conclude that reduced VKOR activity and warfarin resistance in the Japanese black rat might be due to mutations in the VKORC1 gene. However, further study is needed to clarify how such rats can maintain adequate vitamin K-dependent clotting factor levels, while simultaneously exhibiting low VKOR activity and warfarin resistance. (C) 2012 Elsevier Inc. All rights reserved.