Ishizuka Mayumi, Okajima Fumie, Tanikawa Tsutomu, Min Heewon, Tanaka Kazuyuki D, Sakamoto Kentaro Q, Fujita Shoichi
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo 060-0818, Japan.
Drug Metab Dispos. 2007 Jan;35(1):62-6. doi: 10.1124/dmd.106.011775. Epub 2006 Sep 29.
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.
野生屋顶鼠（黑家鼠）生活在靠近人类栖息地的地方，它们可能携带多种传染病病原体。害虫控制对公共卫生很重要，华法林是全球常用的灭鼠剂。然而，持续使用华法林可能会导致啮齿动物产生耐药性并导致灭鼠失败，尤其是在城市化地区。在对华法林耐药的大鼠中，口服给药后血浆中的华法林水平明显低于对照的对华法林敏感的大鼠。华法林由细胞色素P450（P450）代谢，在对华法林耐药的大鼠中，P450同工型对华法林的羟基化作用明显更高（2倍）。蛋白质印迹分析表明，对华法林耐药的大鼠中CYP3A2的表达水平明显高于对华法林敏感的大鼠。耐药大鼠中的NADPH-P450还原酶活性比敏感大鼠高8倍。在体内，给予P450强效抑制剂丙胺太林（SKF-525A）可增加对华法林耐药的屋顶鼠对华法林的死亡率。我们得出结论，东京屋顶鼠对华法林耐药的机制是由华法林清除率增加引起的。
