WARFARIN-BASED RODENTICIDES - MODE OF ACTION AND MECHANISM OF RESISTANCE

Warfarin and related substances have been in use as rodenticides for f ifty years. They act by binding to the enzyme Vitamin K 2,3-epoxide re ductase, thereby interrupting the cellular recycling of vitamin K. Vit amin K in its hydroquinone form is an essential cofactor for the synth esis of functional prothrombin and related blood-clotting factors. The binding with the reductase is essentially irreversible, indicating th ese compounds have a prolonged half-life in target tissues; 7-10 days for warfarin and congeners and over 100 days for the second generation rodenticides or 'superwarfarins' such as difenacoum, brodifacoum, and flocoumafen. Rat liver contains 1-2 nmole of enzyme per gram tissue w hich is a 4-5 fold overcapacity for maintaining effective vitamin K re cycling. The use of warfarin as a rat poison has resulted in the natur al selection of warfarin-resistant rats. The resistance is inheritable . Two distinct warfarin resistance genotypes, Welsh and Scottish, have been identified, clearly differing in their biochemistry of vitamin K epoxide reductase. In the Welsh strain, resistance arises from an alt ered enzyme expressing reduced reactivity to warfarin, whereas the red uctase from the Scottish strain is as sensitive as the normal enzyme, but the interaction with warfarin is now readily reversible. The alter ed enzyme leaves the Welsh rat in need of higher dietary vitamin K int ake. The superwarfarins cope with the resistance by having their struc tures firmly bind with the altered enzymes. Reduced sensitivity to war farin-based rodenticides may also be pharmacokinetically based, arisin g from increased warfarin biotransformation. This mechanism may be res ponsible for resistance to some of the superwarfarins such as difenaco um. A third resistance mechanism may arise from an enhanced capacity t o synthesize vitamin K from menadione, a commonly used additive in ani mal foods on farms. The choice of rodenticide in the case of warfarin resistance should be guided by the underlying mechanism of resistance.