Warfarin-resistant of rats in Japan

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1 Jpn. J. Environ. Toxicol. - Warfarin-resistant of rats in Japan /- /- Kazuyuki TANAKA 1 Tsunehito HARUNARI 2 Tsutomu TANIKAWA 2 Yoshinori IKENAKA 1 and Mayumi ISHIZUKA 2 Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University/Sapporo, - Japan Technical Research Laboratory, IKARI Corporation/ Chibadera Chuo-ku, Chiba, - Japan Warfarin-resistant of rats in Japan ABSTRACT 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 "super rats". Rodenticideresistant 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 VKORC gene were reported in warfarin-resistant rodents. Moreover, the metabolism of warfarin is accelerated in warfarinresistant rats due to the elevation of cytochrome P -dependent xenobiotic metabolizing activities. The combination of a VKOR mutation and P 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.

2 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. Key words: Warfarin resistance, Vitamin K epoxide reductase VKOR cytochrome P450, Rodent NHK.

3 pest control operator: PCO K K a WHO a

4 a g g/ g body weight b b b a a TABLE. Pelz et al.,

5 TABLE 1. Current states of anticoagulant resistance in commensal rats and house mice Hydroxycoumarin target molecule is vitamin K epoxide reductase (VKOR). Warfarin inhibits the function of VKOR, which recycle vitamin K to activate blood coagulant factors, and causes hemorrhage. Fig.1. The effect of warfarin as rodenticide K Stafford K K K K VKOR VKORC Rost et al., ; Li et al., VKOR Fig. Cain et al., ; Furie and Furie, ; Helgeland, ; Suttie, ; Thijssen et al., VKOR VKORC VKOR

6 Rost et al., VKORC VKORC Pelz et al., Vmax/Km VKORKi Lasseur et al., VKORC VKORC VKORC Wallin R & Hutson SM, VKORC VKOR P Fig.2. Metabolic pathway of warfarin. Fig. Ishizuka et al., P CYP A NAPDH P P SKF- A SKF- A Fig.

7 Fig.3. Mechanisms for resistance against anticoagulant rodenticide. It is possible that several mechanisms contribute to warfarin resistance, e.g., modulations of both VKOR and CYP-dependent system. Lund Nahas et al., Chaudhary et al., ; D Tanikawa et al., Integrated Pest Management IPM IPM

8 Integrated Pest Management IPM Cain, D., Hutson, S. and Wallin, R. Warfarin resistance is associated with a protein component of vitamin K, -epoxide reductase enzyme complex in rat liver. Thromb. Haemostasis, : -. Chaudhary, V., Tripathi, R. S. and Poonia, F. S. Effect of supplementary feeding of vitamin K on difethialone treated Indian gerbil, Tatera indica Hardwicke in laboratory. Indian J. Exp. Biol., : -. Furie, B. and Furie, B.C. The molecular basis of blood Coagulation. Cell, : - Gebauer, M. Synthesis and structureactivity relationships of novel warfarin derivatives. Bioorg. Med. Chem.,, -. Helgeland, L. The submicrosomal site for the conversion of prothrombin precursor to biologically active prothrombin in rat liver. Biochem. Biophys. Acta., : -. Ishizuka, M., Okajima, F., Tanikawa, T., Min, H., Tanaka, K.D., Sakamoto, K.Q., Fujita, S. Elevated warfarin metabolism in warfarin-resistant roof rats Rattus rattus in Tokyo. Drug Metab Dispos. : -. Lasseur, R., Longin-Sauvageon, C., Videmann, B., Billeret, M., Berny, P., and Benoit,E. Warfarin resistance in a French strain of rats. J Biochem Mol Toxicol : - Li, T., Chang, C.Y., Jin, D.Y., Lin, P.J., Khvorova, A. and Stafford, D.W. ntification of

9 the gene for vitamin K epoxide reductase. Nature. -. Lund, M. Comparative effect of the three rodenticides warfarin, difenacoum and rodifacoum on eight rodent species in shot feeding periods. J.Hyg., : -. Rattus rattus,, : - Nahas, K., Lorgue, G. and Mazallon, M. Difethialone LM- : a new anticoagulant rodenticide for use against warfarinresistant and susceptible strains of Rattus norvegicus and Mus musculus. Ann. Rech. Vet. : -. Pelz, H.J., Rost, S., Hünerberg, M., Fregin, A., Heiberg, A.C., Baert, K., MacNicoll, A.D., Prescott, C.V., Walker, A.S., Oldenburg, J., Müller, C.R. The genetic basis of resistance to anticoagulants in rodents. Genetics. :-. Rost, S., Fregin, A., Ivaskevicius, V., Conzelmann, E., Hörtnagel, K., Pelz, H.J., Lappegard. K., Seifried. E., Scharrer. I., Tuddenham. E.G..D., Müller, C.R., Strom, T.M. and Oldenburg, J. Mutations in VKORC cause warfarin resistance and multiple coagulation factor deficiency type. Nature, -. Rost, S., Fregin, A., Hünerberg, M., Bevans, C.G., Müller, C.R. and Oldenburg, J. Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC : evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin. Thromb. Haemost., : -. Stafford, D.W. The vitamin K cycle. J. Thromb. Haemost., :-. Suttie, J. Vitamin K-dependent carboxylase. Annu. Rev. Biochem. -. pp - Rattus rattus, : - : - Rattus rattus LFP, -. Rattus rattus : -. : - Tanikawa, T., Inada, E., Kosone, T., Uchida, A. and Kusano, T. Rodenticidal effects of a mixture of warfarin and vitamin D as poison baits. Med.Entomol.Zool., : -. - a Rattus norvegicus : -. b

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