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タイトル
  • en The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan
作成者
    • en Tanaka, Kazuyuki D.
    • en Kawai, Yusuke K.
    • en Harunari, Tsunehito
    • en Tanikawa, Tsutomu
    • en Ando, Shima
    • en Min, Hee Won
    • en Okajima, Fumie
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
    Issued2012-06
言語
  • eng
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
    • PISSN 0048-3575
      • en Pesticide Biochemistry and Physiology
      • 103 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