1998) and other vitamin-K-dependent proteins ( P resnell and S tafford 2002). Vitamin K hydroquinone is an essential cofactor for the post-translational gamma-carboxylation of several blood coagulation factors ( N elsestuen et al. This class of anticoagulants target the vitamin K epoxide reductase (VKOR) complex, which fulfills a basic function in the recycling of vitamin K ( L owenthal and M acfarlane 1964). Today, control of commensal rodents, particularly of brown rats, relies predominantly on the use of anticoagulants.Р”Вuring the same time period, coumarin derivatives have gained a leading role as oral anticoagulants for the treatment and prevention of thromboembolic events in humans. The delayed action of such compounds, with mortality occurring days or even weeks after initial bait uptake makes them particularly suitable for the control of phobic species like brown rats ( Rattus norvegicus). THE introduction of warfarin and related anticoagulant compounds in the early 1950s produced a significant change for rodent control practice. Our findings provide the basis for a DNA-based field monitoring of anticoagulant resistance in rodents. We hypothesize that these mutations, apart from generating structural changes in the VKORC1 protein, may induce compensatory mechanisms to maintain blood clotting. They suggest that mutations in VKORC1 are the genetic basis of anticoagulant resistance in wild populations of rodents, although the mutations alone do not explain all aspects of resistance that have been reported. Our data strongly argue for at least seven independent mutation events in brown rats and two in mice. By recombinant expression of VKORC1 constructs in HEK293 cells we demonstrate that mutations at Tyr139 confer resistance to warfarin at variable degrees while the other mutations, in addition, dramatically reduce VKOR activity. Here, we report on the identification of eight different mutations in the VKORC1 gene in resistant laboratory strains of brown rats and house mice and in wild-caught brown rats from various locations in Europe with five of these mutations affecting only two amino acids (Tyr139Cys, Tyr139Ser, Tyr139Phe and Leu128Gln, Leu128Ser). Resistance is transmitted as an autosomal dominant trait although, until recently, the basic genetic mutation was unknown.

Anticoagulant-resistant rodent populations have been reported from many countries and pose a considerable problem for pest control. These compounds inhibit blood coagulation by repression of the vitamin K reductase reaction (VKOR). Anticoagulant compounds, i.e., derivatives of either 4-hydroxycoumarin ( e.g., warfarin, bromadiolone) or indane-1,3-dione ( e.g., diphacinone, chlorophacinone), have been in worldwide use as rodenticides for >50 years.

1993 roof rats game