The vitamin K epoxide reductase and its role in warfarin resistance.

摘要

Vitamin K functions as a cofactor in the post translational {dollar}gamma{dollar}-carboxylation of specific glutamyl residues in certain protein precursors, including the blood coagulation factors II, VII, IX and X. During the carboxylation reaction, vitamin K hydronaphthoquinone is converted to vitamin K epoxide. The vitamin K epoxide is recycled back to the active, hydronaphthoquinone form of the vitamin through the actions of the vitamin K epoxide reductase, and various quinone reductases.; Warfarin (3-{dollar}alpha{dollar}-acetonylbenzyl-4-hydroxycoumarin) is a potent anticoagulant and rodenticide. It prevents the recycling of the epoxide back to the hydronaphthoquinone form of the vitamin by inhibiting the vitamin K epoxide reductase and dithiol-dependent quinone reductase. Due to the widespread use of warfarin as a rodenticide, warfarin resistant rat and mouse strains have been identified.; A warfarin resistant strain of rats from Chicago was examined to determine its mechanism of warfarin resistance. The rats were found to have an epoxide reductase that was sensitive to warfarin inhibition, but unlike with the normal enzyme, the inhibition was partially reversible. The rate of warfarin clearance from the liver microsomes was also increased.; Mice resistant to warfarin and bromadiolone (another 4-hydroxycoumarin) were examined and found to possess an epoxide reductase that was, in some cases, highly resistant to warfarin inhibition (which is analogous to the situation in a Welsh strain (HW) of warfarin resistant rats). Some of the mice, however, possessed an epoxide reductase that was only slightly less sensitive to warfarin inhibition than normal. Whether this inhibition is reversible, like it is with the epoxide reductase from the Chicago resistant rats, has yet to be determined.; The sensitivity of the HW rat epoxide reductase to different sulfhydryl reagents and coumarins was explored in order to gain insight into how the enzyme had been altered. The HW rat epoxide reductase was less sensitive to inhibition by the various coumarins examined, but it was more sensitive to inhibition by the sulfhydryl reagents. The epoxide reductase has not been purified, but a number of techniques that might be useful in further purification of the enzyme were explored.