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First published on September 29, 2006; DOI: 10.1124/dmd.106.011775

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Received for publication July 7, 2006.
Revised September 26, 2006.
Accepted for publication September 27, 2006.

Elevated warfarin metabolism in warfarin-resitant roof rats (Rattus rattus) in Tokyo

Mayumi Ishizuka 1, Fumie Okajima 1, Tsutomu Tanikawa 2, Heewon Min 1, Kazuyuki D Tanaka 1, Kentaro Q Sakamoto 1, Shoichi Fujita 1*

1 Graduate School of Veterinary Medicine, Hokkaido University 2 Technical Research Laboratory, IKARI Corporation

* Address correspondence to: E-mail: ishizum{at}vetmed.hokudai.ac.jp

Abstract

Wild roof rats (Rattus rattus) live in proximity to human habitats, and they may carry numerous pathogens of infectious diseases. The 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 (CYP), and hydroxylations of warfarin by CYP isoforms were significantly higher in warfarin-resistant rats (2-fold). Western blot analysis indicated that the level of CYP3A2 expression in warfarin-resistant rats were significantly larger than in warfarin-sensitive rats. The NADPH-P450 reductase activities in resistant rats were 8-fold higher than those in sensitive rat. In vivo, the administration of P450 potent inhibitor 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.


Key words: CYP induction, cytochrome P450, environmental toxicology




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