Warfarin-resistant of rats in Japan

Warfarin is commonly used worldwide as a rodenticide. Warfarin inhibits blood coagulation, and continuous intake of warfarin causes potentially fatal hemorrhages. However, warfarin-resistant roof rats（Rattus rattus）are found in Japan, especially in the Tokyo area. Recently, warfarin-resistant brown rats（Rattus norvegicus）were discovered in rural areas of Japan. Warfarin-resistant house mice have not been reported, but it is highly possible that resistant mice will be also found in our country. Warfarin-resistant rats, which have acquired resistance to anticoagulant rodenticides, are called &ｌquot;super rats&ｒquot;. Rodenticide-resistant roof rats, brown rats, and house mice have been also reported in the United States and European countries, e.g., Britain, France, Denmark, and Germany. In addition, warfarin-resistant rodents may be widespread in other countries that have not been investigated yet. The warfarin target molecule is vitamin K epoxide reductase（VKOR）．Warfarin inhibits the function of VKOR, which recycles vitamin K to activate blood coagulant factors, and causes hemorrhage. Substitutions in the VKORC1 gene were reported in warfarin-resistant rodents. Moreover, the metabolism of warfarin is accelerated in warfarin-resistant rats due to the elevation of cytochrome P450-dependent xenobiotic metabolizing activities. The combination of a VKOR mutation and P450 acceleration causes warfarin resistance in wild rodents, which is an evolutionary adaptation to the pesticide-polluted environment. After the appearance of warfarin-resistant rodents, a second-generation rodenticide was developed and replaced warfarin in Europe and America. In Japan, difethialone is the only the second-generation rodenticide that can be used in public buildings. In Japan, a critical zoonosis infection has not yet spread on a large scale through wild rodents. However, it is necessary to consider how to prevent serious infestation by house rodents in the industrial, administrative, and academic sectors before such infestation occurs.