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The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan

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Title: The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan
Authors: Tanaka, Kazuyuki D. Browse this author
Kawai, Yusuke K. Browse this author
Ikenaka, Yoshinori Browse this author →KAKEN DB
Harunari, Tsunehito Browse this author
Tanikawa, Tsutomu Browse this author
Ando, Shima Browse this author
Min, Hee Won Browse this author
Okajima, Fumie Browse this author
Fujita, Shoichi Browse this author →KAKEN DB
Ishizuka, Mayumi Browse this author →KAKEN DB
Keywords: Warfarin resistance
Rattus rattus
Vitamin K epoxide reductase
VKOR activity
Coagulation time
Issue Date: Jun-2012
Publisher: Elsevier
Journal Title: Pesticide Biochemistry and Physiology
Volume: 103
Issue: 2
Start Page: 144
End Page: 151
Publisher DOI: 10.1016/j.pestbp.2012.04.011
Abstract: 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.
Type: article (author version)
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 石塚 真由美

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