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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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Fig1 warfarin metabolic pathway-6.pdf31.89 kBPDFView/Open
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Fig3 in vitro revised.pdf101.28 kBPDFView/Open
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Pesticide biochemistry and physiology148_42-49.pdf421.07 kBPDFView/Open
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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
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.
Type: article (author version)
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)

Submitter: 石塚 真由美

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