Novel Variants in VKORC1 - the Target Protein of Cumarin-Type Anticoagulants - in Rodents from Warfarin-Resistance Areas in Europe, Asia and America

摘要

Coumarin derivatives, e.g. Warfarin, are in world-wide use as effective anticoagulants for therapy of thrombo-embolic diseases in humans as well as for rodent pest control since they effectively inhibit blood coagulation. However, patients under anticoagulant therapy as well as rodent populations have developed resistance to Cumarins soon after the introduction of these compounds. Today, in many countries, effective rodent pest control is hampered by the rapid spreading of Warfarin-resistant populations.Recently, the target enzyme for Coumarins has been identified: VK0RC1 (vitamin K epoxide reductase complex subunit 1), the key component of the vitamin K redox cycle, is capable of reducing vitamin K epoxide and is inhibited by Warfarin. Mutations in VK0RC1 have been shown to confer resistance (in vivo and in vitro) to anticoagulants of the Coumarin-type in humans and rodents. In rats and mice independent mutations have arisen in different Warfarin-resistance areas throughout the world and affect different amino acid positions of the VKORC1 protein.