Warfarin resistance in a French strain of rats

Authors

  • Romain Lasseur,

    1. UMR 1233 INRA/DGER, Métabolisme des Xénobiotiques et Mycotoxines, National Veterinary School of Lyon, BP 83, 69280 Marcy l'Etoile, France
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  • Christiane Longin-Sauvageon,

    1. UMR 1233 INRA/DGER, Métabolisme des Xénobiotiques et Mycotoxines, National Veterinary School of Lyon, BP 83, 69280 Marcy l'Etoile, France
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  • Bernadette Videmann,

    1. UMR 1233 INRA/DGER, Métabolisme des Xénobiotiques et Mycotoxines, National Veterinary School of Lyon, BP 83, 69280 Marcy l'Etoile, France
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  • Mikaëline Billeret,

    1. LiphaTech, BP3, 47480 Pont du Casse, France
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  • Philippe Berny,

    1. UMR 1233 INRA/DGER, Métabolisme des Xénobiotiques et Mycotoxines, National Veterinary School of Lyon, BP 83, 69280 Marcy l'Etoile, France
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  • Etienne Benoit

    Corresponding author
    1. UMR 1233 INRA/DGER, Métabolisme des Xénobiotiques et Mycotoxines, National Veterinary School of Lyon, BP 83, 69280 Marcy l'Etoile, France
    • UMR 1233 INRA/DGER, Métabolisme des Xénobiotiques et Mycotoxines, National Veterinary School of Lyon, BP 83, 69280 Marcy l'Etoile, France
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Abstract

A warfarin-resistant strain and a warfarin-susceptible strain of wild rats (Rattus norvegicus) maintained in enclosures of the National Veterinary School of Lyon (France) were studied to determine the mechanism of the resistance to anticoagulant rodenticides. A low vitamin K epoxide reductase (VKOR) activity has been reported for many resistant rat strains. As recently suggested, mutations in the vitamin K epoxide reductase subunit 1 (VKORC1) gene are the genetic basis of anticoagulant resistance in wild populations of rats from various locations in Europe. Here we report, for our strain, one of the seven described mutations (Tyr139Phe) for VKORC1 in rats. In addition, a low expression of mRNA encoding VKORC1 gene is observed in resistant rats, which could explain their low VKOR activity. We calculated kinetic parameters of VKOR in the warfarin-resistant and warfarin-susceptible rats. The Vmax and the Km of the VKOR obtained in resistant rats were lowered by 57 and 77%, respectively, compared to those obtained in susceptible rats. As a consequence, the enzymatic efficiency (Vm/Km) of the VKOR was similar between resistant and susceptible rats. This result could be a good explanation to the observation that no clinical signs of vitamin K deficiency was observed in the warfarin-resistant strain, while a low VKOR activity was found. VKOR activity in warfarin-resistant rats was poorly inhibited by warfarin (Ki for warfarin is 29 μM and 0.72 μM for resistant and susceptible rats, respectively). © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:379-385, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20104

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