Consequences of the Y139F Vkorc1 mutation on resistance to AVKs: in-vivo investigation in a 7th generation of congenic Y139F strain of rats.
OBJECTIVE
In humans, warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events. Warfarin derivatives are also used as rodenticides in pest control. The gene encoding the protein targeted by anticoagulants is the Vitamin K-2,3-epoxide reductase subunit 1 (VKORC1). Since its discovery in 2004, various amino acid and transcription-regulatory altering VKORC1 mutations have been identified in patients who required extreme antivitamin K dosages, or wild populations of rodents that were difficult to control with anticoagulant rodenticides. One unresolved question concerns the dependency of the VKORC1 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants. Moreover, an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives (superwarfarins).


METHODS
In this study, we bred a quasicongenic rat strain by using a wild-caught anticoagulant resistant rat as a donor to introduce the Y>F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque-Dawley recipient strain.


CONCLUSIONS
In this manuscript we report the prothrombin times measured in the F7 generation after exposure to chlorophacinone, bromadiolone, difenacoum and difethialone. We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone. However, the physiological response to the super-warfarins, difenacoum and difethialone, may be strongly dependent on other genes located outside the congenic interval (28.3 cM) bracketing the Vkorc1 in our F7 generation congenic strain.
Grandemange
Agnes
A
UMR INRA/ENVL Metabolisme des Xenobiotiques et Mycotoxines Universite Lyon, Bonnel, Pont du Casse, France.
Kohn
Michael Hans
MH
Lasseur
Romain
R
Longin-Sauvageon
Christiane
C
Berny
Philippe
P
Benoit
Etienne
E
D015110:4-Hydroxycoumarins / Q000494:pharmacology*; D000818:Animals; D020296:Animals, Congenic; D000925:Anticoagulants / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D007192:Indenes / Q000494:pharmacology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D012378:Rodenticides / Q000494:pharmacology; D014812:Vitamin K / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology
D015110:4-Hydroxycoumarins; D000925:Anticoagulants; D007192:Indenes; D012378:Rodenticides; C011664:antivitamins K; D014812:Vitamin K; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases