Journal
BLOOD ADVANCES
Volume 4, Issue 10, Pages 2202-2212Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2020001750
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Funding
- National Institutes of Health, National Heart, Lung, and Blood Institute [R01 HL121718]
- W. M. Keck Foundation
- Children's Discovery Institute [MC-II-2020-854]
- National Institutes of Health, National Eye Institute [R21 EY028705]
- National Institutes of Health, National Institute of General Medical Sciences [P41 GM103422, R01 GM131008]
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Dose control of warfarin is a major complication in anticoagulation therapy and overdose is reversed by the vitamin K antidote. Improving the dosage management and antidotal efficacy requires mechanistic understanding. Here we find that effects of the major predictor of warfarin dosage, SNP -1639 G>A, follow a general correlation that warfarin 50% inhibitory concentration decreases with cellular level of vitamin K epoxide reductase (VKORC1), suggesting stoichiometric inhibition. Characterization of the inhibition kinetics required the use of microsomal VKORC1 with a native reductant, glutathione, that enables effective warfarin inhibition in vitro. The kinetics data can be fitted with the Morrison equation, giving a nanomolar inhibition constant and demonstrating that warfarin is a tight-binding inhibitor. However, warfarin is released from purified VKORC1-warfarin complex with increasing amount of vitamin K, indicating competitive inhibition. The competition occurs also in cells, resulting in rescued VKORC1 activity that augments the antidotal effects of vitamin K. Taken together, warfarin is a competitive inhibitor that binds VKORC1 tightly and inhibits at a stoichiometric (1:1) concentration, whereas exceeding the VKORC1 level results in warfarin overdose. Thus, warfarin dosage control should use VKORC1 level as a major indicator, and improved antidotes may be designed based on their competition with warfarin.
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