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

Tanaka, Kazuyuki D.; Kawai, Yusuke K.; Ikenaka, Yoshinori; Harunari, Tsunehito; Tanikawa, Tsutomu; Ando, Shima; Min, Hee Won; Okajima, Fumie; Fujita, Shoichi; Ishizuka, Mayumi

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

Tanaka, Kazuyuki D.; Kawai, Yusuke K.; Ikenaka, Yoshinori et al.

Pesticide Biochemistry and Physiology, 2012, 103(2), 144-151

Permalink : https://hdl.handle.net/2115/49676

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アクセス権	open access
URI	https://hdl.handle.net/2115/49676
タイトル	The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan
著者	Tanaka, Kazuyuki D. ; Kawai, Yusuke K. ; Ikenaka, Yoshinori ; Harunari, Tsunehito ; Tanikawa, Tsutomu ; Ando, Shima ; Min, Hee Won ; Okajima, Fumie ; Fujita, Shoichi ; Ishizuka, Mayumi
著者名 Tanaka, Kazuyuki D.
著者名 Kawai, Yusuke K.
e-Rad_Researcher 40543509 著者名 Ikenaka, Yoshinori
著者名 Harunari, Tsunehito
著者名 Tanikawa, Tsutomu
著者名 Ando, Shima
著者名 Min, Hee Won
著者名 Okajima, Fumie
e-Rad_Researcher 10143314 著者名 Fujita, Shoichi
e-Rad_Researcher 50332474 著者名 Ishizuka, Mayumi
言語	英語
キーワード	Warfarin resistance
	Rattus rattus
	Vitamin K epoxide reductase
	VKOR activity
	Coagulation time
発行日	2012-06
出版者	Elsevier
収録物名	Pesticide Biochemistry and Physiology
巻(号)	103(2)
ページ	144-151
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
PISSN	0048-3575
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.pestbp.2012.04.011