Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan; Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa.
Pestic Biochem Physiol. 2018 Jun;148:42-49. doi: 10.1016/j.pestbp.2018.03.018. Epub 2018 Apr 1.
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 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.
抗凝血杀鼠剂，如华法林，已在全球范围内使用。它们抑制维生素 K 环氧化物还原酶（VKOR），VKOR 对于产生几种凝血因子是必需的。杀鼠剂的这种抑制作用会导致啮齿动物致命性出血。然而，这些药物的大量使用导致了抗杀鼠剂老鼠的出现。这种抗性有两个主要机制，即华法林的靶酶 VKOR 的突变和华法林代谢的增强。然而，关于华法林的肝代谢，应该与抗性有关，这方面的研究很少。为了研究抗性大鼠中华法林的代谢情况，用来自日本东京的抗性黑鼠（Rattus rattus）进行了华法林原位肝脏灌注。肝脏灌注是一种原位方法，可以用肝脏的天然成分特异性地揭示肝脏功能。结果表明，与敏感黑鼠相比，肝脏对华法林的羟化活性增强。另一方面，在体外微粒体华法林代谢测定中，研究细胞色素 P450 的动力学参数，细胞色素 P450 在华法林羟化中起主要作用，与原位研究相比，抗性大鼠的 V 值略高但具有显著性差异。这些结果表明，除了细胞色素 P450 的高表达外，另一种如电子供体的因素也可能有助于增强代谢。
