Abstract
A warfarin-resistant strain of rats trapped in Chicago was studied to determine the mechanism of the warfarin resistance. The Chicago-resistant rats (CR) differ from a Welsh-resistant strain (WR) which has a vitamin K epoxide reductase that is insensitive to warfarin. The epoxide and dithioldependent quinone reductases of the CR rats were as sensitive to warfarin as the normal enzyme. Unlike the irreversible warfarin inhibition seen in normal rats, the warfarin inhibition of the epoxide reductase from the CR strain was partially reversible in vitro. In this respect, the CR rats appeared similar to a Scottish warfarin-resistant strain. The same steady-state level of warfarin (40 ng/mg protein) in liver microsomes could be achieved in normal and CR strain rats following a few days ingestion of a diet containing 50 ppm warfarin, but clearance of warfarin (l mg/kg) from the liver microsomes was more rapid in the CR strain than in normal rats, and the recovery of epoxide reductase activity and prothrombin levels was more rapid. The mechanism of warfarin resistance in the CR strain differed from the warfarin resistance mechanisms of both the Scottish- and Welsh-resistant rat strains. The combination of an increased rate of warfarin clearance and the partially reversible inhibition of the epoxide reductase would be sufficient to allow the rats to survive a limited exposure to warfarin.
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