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.