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Background  Coumarin derivatives have been in world-wide use for rodent pest control for more than 50 years. Due to their retarded action as inhibitors of blood coagulation by repression of the vitamin K reductase (VKOR) activity, they are the rodenticides of choice against several species. Resistance to these compounds has been reported for rodent populations from many countries around the world and poses a considerable problem for efficacy of pest control.    Results  In the present study, we have sequenced the  VKORC1  genes of more than 250 rats and mice trapped in anticoagulant-exposed areas from four continents, and identified 18 novel and five published missense mutations, as well as eight neutral sequence variants, in a total of 178 animals. Mutagenesis in  VKORC1  cDNA constructs and their recombinant expression revealed that these mutations reduced VKOR activities as compared to the wild-type protein. However, the  in vitro  enzyme assay used was not suited to convincingly demonstrate the warfarin resistance of all mutant proteins    Conclusion  Our results corroborate the  VKORC1  gene as the main target for spontaneous mutations conferring warfarin resistance. The mechanism(s) of how mutations in the  VKORC1  gene mediate insensitivity to coumarins  in vivo  has still to be elucidated.

Novel mutations in the VKORC1 gene of wild rats and mice – a response to 50 years of selection pressure by warfarin?