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Investigation of hepatic warfarin metabolism activity in rodenticide-resistant black rats (Rattus rattus) in Tokyo by in situ liver perfusion
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| Title: | Investigation of hepatic warfarin metabolism activity in rodenticide-resistant black rats (Rattus rattus) in Tokyo by in situ liver perfusion |
| Authors: | Takeda, Kazuki Browse this author | | Ikenaka, Yoshinori Browse this author →KAKEN DB | | Tanaka, Kazuyuki D. Browse this author | | Nakayama, Shouta M. M. Browse this author →KAKEN DB | | Tanikawa, Tsutomu Browse this author | | Mizukawa, Hazuki Browse this author →KAKEN DB | | Ishizuka, Mayumi Browse this author →KAKEN DB |
| Keywords: | Warfarin | | Rodenticide resistance | | Rattus rattus | | Liver perfusion | | Metabolism | | Cytochrome P450 |
| Issue Date: | Jun-2018 |
| Publisher: | Elsevier |
| Journal Title: | Pesticide biochemistry and physiology |
| Volume: | 148 |
| Start Page: | 42 |
| End Page: | 49 |
| Publisher DOI: | 10.1016/j.pestbp.2018.03.018 |
| PMID: | 29891376 |
| Abstract: | Anti-blood coagulation rodenticides, such as warfarin, have been used all over the world. They inhibit vitamin K epoxide reductase (VKOR), which is necessary for producing several blood clotting factors. This inhibition by rodenticides results in lethal hemorrhage in rodents. However, heavy usage of these agents has led to the appearance of rodenticide-resistant rats. There are two major mechanisms underlying this resistance, i.e., mutation of the target enzyme of warfarin, VKOR, and enhanced metabolism of warfarin. However, there have been few studies regarding the hepatic metabolism of warfarin, which should be related to resistance. To investigate warfarin metabolism in resistant rats, in situ liver perfusion of warfarin was performed with resistant black rats (Rattus rattus) from Tokyo, Japan. Liver perfusion is an in situ methodology that can reveal hepatic function specifically with natural composition of the liver. The results indicated enhanced hepatic warfarin hydroxylation activity compared with sensitive black rats. On the other hand, in an in vitro microsomal warfarin metabolism assay to investigate kinetic parameters of cytochrome P450, which plays a major role in warfarin hydroxylation, the V-max of resistant rats was slightly but significantly higher compared to the results obtained in the in situ study. These results indicated that another factor like electron donators may also contribute to the enhanced metabolism in addition to high expression of cytochrome P450. |
| Rights: | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/74573 |
| Appears in Collections: | 獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 石塚 真由美
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