title: Pesticide resistance in wild mammals--mechanisms of anticoagulant resistance in wild rodents.
abstract: Warfarin is commonly used worldwide as a rodenticide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. It has been reported that repeated or long-term treatments with this drug cause resistance in wild rodents. However, the mechanism of warfarin resistance in rodents is still not known precisely. Recent studies reported and identified the function of the molecule, vitamin K epoxide reductase complex subunit 1 (VKORC1), which is the main unit of VKOR. An amino acid substitution in VKORC1 is one of the supposed mechanisms of warfarin resistance. An accelerated detoxification system involving cytochrome P450 (CYP) could also cause the rodenticide resistance. Administration of SKF-525A, a potent inhibitor for P450, increased the mortality due to reduction of warfarin metabolism in warfarin-resistant rats. Meanwhile, the appearance of warfarin-resistant rodents has led to the development of the more effective and toxic rodenticide superwarfarin, which is widely used in Europe and the USA. However, animals resistant to this second-generation rodenticide have already been reported in Europe. In this review, we focus on the mechanism and the pleiotropic effects of pesticide resistance in wild rodents.
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo. ishizum@vetmed.hokudai.ac.jp
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanikawa
authors.forename: Kazuyuki D
authors.initials: KD
authors.lastname: Tanaka
authors.forename: Min
authors.initials: M
authors.lastname: Heewon
authors.forename: Fumie
authors.initials: F
authors.lastname: Okajima
authors.forename: Kentaro Q
authors.initials: KQ
authors.lastname: Sakamoto
authors.forename: Shoichi
authors.initials: S
authors.lastname: Fujita
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004351:Drug Resistance; D006899:Mixed Function Oxygenases / Q000235:genetics; D009154:Mutation; D051381:Rats; D012378:Rodenticides / Q000494:pharmacology*; D014812:Vitamin K / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D012378:Rodenticides; D014812:Vitamin K; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases