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Abstract
Warfarin-susceptible and warfarin-resistant Norway rat (Rattus norvegicus) strains from France were studied to determine the mechanism of resistance to warfarin. As recently suggested by other authors, mutations in the vitamin K epoxide reduction subunit 1 (VKORC1) gene are the basis anticoagulant resistance. We found one of the seven previously described mutations (Y139F) for VKORC1, and calculated the kinetic parameters of vitamin K epoxide reductase (VKOR) in resistant (homozygous for Y139F) and susceptible rats. In resistant rats, VKOR activity was lower and also less inhibited by warfarin (20 μM) than in susceptible rats. Difethialone (20 μM) inhibited VKOR activity in both strains. The maximum rate (V max) and affinity constant (K m) of the VKOR in resistant rats was lowered compared to those obtained in susceptible rats. Consequently, the enzymatic efficiency (V m/K m) of the VKOR was similar between resistant and susceptible rats. VKOR activity in warfarin-resistant rats was poorly inhibited by warfarin. A low expression of mRNA encoding the VKORC1 gene was observed in resistant rats. These findings appear to support the hypothesis that several different mechanisms are involved in warfarin resistance in the strain of Rattus norvegicus we studied.
Acknowledgements
The authors wish to thank A. Bourret and F. Peigneaux for their technical assistance and R. Sullivan for help in the manuscript correction. This research was supported by the INRA (Institut National de la Recherche Agronomique) and the DGER (Direction Generale de l'Enseignement et de la Recherche).
Notes
*Animals were killed be decapitation after anesthesia with isoflumne, in accordance with French regulations, in application of the EU Directive 86/609 and each protocol was reviewed by the local ethics committee.