タイトル |
-
en
The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan
|
作成者 |
|
アクセス権 |
open access |
主題 |
-
Other
en
Warfarin resistance
-
Other
en
Rattus rattus
-
Other
en
Vitamin K epoxide reductase
-
Other
en
VKOR activity
-
Other
en
Coagulation time
-
NDC
649
|
内容注記 |
-
Abstract
en
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 warfarin-resistant 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 Vmax/Km 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.
|
出版者 |
en
Elsevier
|
日付 |
|
言語 |
|
資源タイプ |
journal article |
出版タイプ |
AM |
資源識別子 |
HDL
http://hdl.handle.net/2115/49676
|
関連 |
-
isVersionOf
DOI
https://doi.org/10.1016/j.pestbp.2012.04.011
|
収録誌情報 |
-
-
en
Pesticide Biochemistry and Physiology
-
巻103
号2
開始ページ144
終了ページ151
|
ファイル |
|
コンテンツ更新日時 |
2023-07-26 |