title: Biochemical characterization of spontaneous mutants of rat VKORC1 involved in the resistance to antivitamin K anticoagulants.
abstract: Antivitamin K anticoagulants have been commonly used to control rodent pest all over the world for more than 50 years. These compounds target blood coagulation by inhibiting the vitamin K epoxide reductase (VKORC1), which catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K. Resistance to anticoagulants has been reported in wild rat populations from different countries. From these populations, several mutations of the rVkorc1 gene have been reported. In this study, rat VKORC1 and its most frequent mutants L120Q-, L128Q-, Y139C-, Y139S- and Y139F-VKORC1 were expressed as membrane-bound proteins in Pichia pastoris and characterized by the determination of kinetic and inhibition parameters. The recombinant rVKORC1 showed similar properties than those of the native proteins expressed in the rat liver microsomes, validating the expression system as a good model to study the consequences of VKORC1 mutations. The determination of the inhibition parameters towards various antivitamin K anticoagulants demonstrated that mutations at Leu-120, Leu-128 and Tyr-139 confer the resistance to the first generation AVKs observed in wild rat populations.
authors: USC 1233 INRA/Vetagro Sup, Mycotoxines et Toxicologie Comparée des Xénobiotiques, Veterinary School of Lyon, 1 av. Bourgelat, Marcy l'Etoile, France.
authors: Ahmed
authors: A
authors: Hodroge
authors: Christiane
authors: C
authors: Longin-Sauvageon
authors: Isabelle
authors: I
authors: Fourel
authors: Etienne
authors: E
authors: Benoit
authors: Virginie
authors: V
authors: Lattard
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D051381:Rats; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases