A Novel Mutation in VKORC1 and Its Effect on Enzymatic Activity in Japanese Warfarin-Resistant Rats
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概要
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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. Hepatic microsomal VKOR-dependent activity was measured over a range of vitamin K epoxide concentrations from 6.25 to 150 μM. The Vmax values of resistant rats (0.0029 ± 0.020 nmol/min/mg) were about one tenth of those of sensitive rats (0.29 ± 0.12 nmol/min/mg). The Km values of resistant rats (47 ± 32 μM) were similar to those of sensitive rats (59 ± 18 μM). Warfarin-sensitive rats exhibited enzyme efficiencies (Vmax/Km) which were ten-fold greater than those observed in resistant rats. It may mean that VKOR activity of warfarin-resistant Aomori rats is almost lost, because their enzymatic efficiencies are very low even without warfarin. Further studies are needed to clarify how these rats can survive with a markedly reduced VKOR activity and how they simultaneously exhibit warfarin resistance.
著者
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Ishizuka Mayumi
Laboratory Of Toxicology
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Tanikawa Tsutomu
Technical Research Laboratory
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Fujita Shoichi
Laboratory Of Toxicology
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Tanaka Kazuyuki
Laboratory Of Toxicology Graduate School Of Veterinary Medicine Hokkaido University
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KAWAI Yusuke
Laboratory of Toxicology, Department of Environmental Veterinary Science, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo, Hokkaido 060–0818, Japan
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FUJITA Shoichi
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo, Hokkaido 060–0818, Japan
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TANIKAWA Tsutomu
Technical Research Laboratory, Ikari Corporation, Chiba 260–0844, Japan
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IKENAKA Yoshinori
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Sapporo 060–0818, Japan
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IKENAKA Yoshinori
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo, Hokkaido 060–0818, Japan
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HARUNARI Tsunehito
Technical Research Laboratory, Ikari Corporation, Chiba 260–0844, Japan
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ISHIZUKA Mayumi
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo, Hokkaido 060–0818, Japan
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