Misenheimer T M, Lund M, Baker E M, Suttie J W
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706.
Biochem Pharmacol. 1994 Feb 11;47(4):673-8. doi: 10.1016/0006-2952(94)90130-9.
Danish mice (Mus musculus domesticus) genetically resistant to the anticoagulant action of two 4-hydroxycoumarins, warfarin and bromadiolone, were examined to determine their mechanism of resistance. The hepatic vitamin K epoxide reductase in the bromadiolone-resistant mice and in one phenotype of warfarin-resistant mice was highly insensitive to in vitro inhibition by warfarin and bromadiolone. The kinetic constants for the epoxide reductase from bromadiolone-resistant mice were also altered. The Vmax for this enzyme was decreased by 40%, and the Km for the reaction reductant, dithiothreitol, was 70% lower than that of normal mice. This phenotype of Danish resistant mice appears to have a resistance mechanism that is similar to that reported for a Welsh strain of warfarin-resistant rats. The other phenotype of Danish resistant mice had a hepatic epoxide reductase that was only slightly less sensitive to warfarin inhibition than normal. The mechanism of warfarin resistance in these mice is not apparent from the available data.
对具有遗传抗性、能抵抗两种4-羟基香豆素（华法林和溴敌隆）抗凝作用的丹麦小鼠（小家鼠）进行了研究，以确定其抗性机制。溴敌隆抗性小鼠和一种华法林抗性小鼠表型中的肝脏维生素K环氧化物还原酶对华法林和溴敌隆的体外抑制高度不敏感。溴敌隆抗性小鼠的环氧化物还原酶的动力学常数也发生了改变。该酶的Vmax降低了40%，反应还原剂二硫苏糖醇的Km比正常小鼠低70%。丹麦抗性小鼠的这种表型似乎具有一种抗性机制，类似于报道的一种威尔士品系的华法林抗性大鼠的抗性机制。丹麦抗性小鼠的另一种表型的肝脏环氧化物还原酶对华法林抑制的敏感性仅略低于正常小鼠。从现有数据来看，这些小鼠对华法林的抗性机制尚不明确。
