Biochemical basis of warfarin and bromadiolone resistance in the house mouse, Mus musculus domesticus.
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.
Misenheimer
T M
TM
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706.
Lund
M
M
Baker
E M
EM
Suttie
J W
JW
D015110:4-Hydroxycoumarins / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D051379:Mice / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D012378:Rodenticides / Q000494:pharmacology*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D015110:4-Hydroxycoumarins; D012378:Rodenticides; D014859:Warfarin; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; C021636:bromadiolone