title: Elevated warfarin metabolism in warfarin-resistant roof rats (Rattus rattus) in Tokyo.
abstract: Wild roof rats (Rattus rattus) live in proximity to human habitats, and they may carry numerous pathogens of infectious diseases. Pest control is important for public health, and warfarin is a commonly used rodenticide worldwide. However, continual use of warfarin may cause drug resistance in rodents and lead to failure of their control, especially in urbanized areas. In warfarin-resistant rats, the warfarin level in plasma was significantly lower after oral administration than that in the control warfarin-sensitive rats. Warfarin is metabolized by cytochrome P450 (P450), and hydroxylation of warfarin by P450 isoforms was significantly higher in warfarin-resistant rats (2-fold). Western blot analysis indicated that the level of CYP3A2 expression in warfarin-resistant rats was significantly larger than in warfarin-sensitive rats. The NADPH-P450 reductase activities in resistant rats were 8-fold higher than those in sensitive rats. In vivo, the administration of the P450 potent inhibitor proadifen (SKF-525A) increased the mortality of warfarin in the warfarin-resistant roof rats. We concluded that the mechanism of warfarin resistance in Tokyo roof rats is caused by increased clearance of warfarin.
authors.affiliation: Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo 060-0818, Japan. ishizum@vetmed.hokudai.ac.jp
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
authors.forename: Fumie
authors.initials: F
authors.lastname: Okajima
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanikawa
authors.forename: Heewon
authors.initials: H
authors.lastname: Min
authors.forename: Kazuyuki D
authors.initials: KD
authors.lastname: Tanaka
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 / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D012378:Rodenticides / Q000493:pharmacokinetics*; D013739:Testosterone / Q000378:metabolism; D014041:Tokyo; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D004791:Enzyme Inhibitors; D012378:Rodenticides; D013739:Testosterone; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D009251:NADPH-Ferrihemoprotein Reductase