Advance Publication The Journal of Veterinary Medical Science Accepted Date: 8 Sep 2012 J-STAGE Advance Published Date: 26 Sep 2012 Field of paper: toxicology Type of paper: full paper A novel mutation in VKORC1 and its effect on enzymatic activity in Japanese warfarin-resistant rats Kazuyuki D. Tanaka1), Yusuke K. Kawai1), Yoshinori Ikenaka1), Tsunehito Harunari2), Tsutomu Tanikawa2), Shoichi Fujita1), and Mayumi Ishizuka1), 1)Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan 2)Technical Research laboratory, Ikari Corporation, Chiba, 260-0844, Japan Corresponding author: Dr. Mayumi Ishizuka, Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan, Tel:81-11-706-6949 / Fax:81-11-706-5105 e-mail:
[email protected] Running head: VKOR OF WARFARIN RESISTANT RATS IN JAPAN 1 ABSTRACT Warfarin is a rodenticide commonly used worldwide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. Recently, warfarin-resistant brown rats (Rattus norvegicus) were found around the Aomori area of Japan. There is no significant difference in the metabolic activity of warfarin in sensitive and resistant brown rats. To clarify the mechanism underlying warfarin resistance, we cloned the VKORC1 gene from rats and identified a novel substitution of arginine to proline at position 33 of the VKORC1 amino acid sequence. Then, we determined the differences in kinetics of VKOR activity between warfarin-resistant and sensitive rats.