Vitamin K epoxide reductase: moving closer to nature
| Autor: | Martin J. Shearer |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Vitamin K Chemistry Immunology Cell Mutant Antagonist Anticoagulants Cell Biology Hematology 030204 cardiovascular system & hematology Vitamin k Biochemistry Thrombosis and Hemostasis 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Oxidoreductase Vitamin K Epoxide Reductases medicine Vitamin K epoxide reductase |
| Zdroj: | Blood. 132:1867-1869 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2018-08-869578 |
| Popis: | Warfarin, acenocoumarol, phenprocoumon, and fluindione are commonly prescribed oral anticoagulants for the prevention and treatment of thromboembolic disorders. These anticoagulants function by impairing the biosynthesis of active vitamin K–dependent coagulation factors through the inhibition of vitamin K epoxide reductase (VKOR). Genetic variations in VKOR have been closely associated with the resistant phenotype of oral anticoagulation therapy. However, the relative efficacy of these anticoagulants, their mechanisms of action, and their resistance variations among naturally occurring VKOR mutations remain elusive. Here, we explored these questions using our recently established cell-based VKOR activity assay with the endogenous VKOR function ablated. Our results show that the efficacy of these anticoagulants on VKOR inactivation, from most to least, is: acenocoumarol > phenprocoumon > warfarin > fluindione. This is consistent with their effective clinical dosages for stable anticoagulation control. Cell-based functional studies of how each of the 27 naturally occurring VKOR mutations responds to these 4 oral anticoagulants indicate that phenprocoumon has the largest resistance variation (up to 199-fold), whereas the resistance of acenocoumarol varies the least ( |
| Databáze: | OpenAIRE |
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