![]() ![]() To regenerate the hydroquinone, VKORC1 reduces the vitamin K epoxide (KO) first to vitamin K quinone (K) and then to KH 2. The carboxylase activity is driven by the epoxidation of vitamin K hydroquinone (KH 2). This cycle occurs in the endoplasmic reticulum (ER) and begins with the γ-carboxylation of selected coagulation factors, a posttranslational modification required for their activity. 8Īs the target of warfarin, VKORC1 supports blood coagulation through the vitamin K cycle. 6, 7, 10 This SNP lowers the messenger RNA (mRNA) and protein levels of VKORC1, and patients carrying this SNP require lower warfarin dosage. 2, 3 The most important predictor of warfarin dosage is the genotype of vitamin K epoxide reductase (VKORC1), 4 - 9 whose promoter region contains a single nucleotide polymorphism (SNP) −1639 G>A that accounts for ∼25% of the interpatient variability. The management of warfarin dosage is further complicated by its wide interindividual variation. As the antidote for the overdose, vitamin K is generally given to restore the coagulation. Underdosing warfarin increases the risk of thrombosis in patients, whereas overdosing often leads to major, even fatal bleeding. 1 Because warfarin has a narrow therapeutic index, effective dosing of this drug requires frequent anticoagulation monitoring and dose adjustments. Warfarin is an oral anticoagulant widely used to treat and prevent thromboembolic diseases. Thus, warfarin dosage control should use VKORC1 level as a major indicator, and improved antidotes may be designed based on their competition with warfarin. 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. The competition occurs also in cells, resulting in rescued VKORC1 activity that augments the antidotal effects of vitamin K. However, warfarin is released from purified VKORC1-warfarin complex with increasing amount of vitamin K, indicating competitive inhibition. The kinetics data can be fitted with the Morrison equation, giving a nanomolar inhibition constant and demonstrating that warfarin is a tight-binding inhibitor. Characterization of the inhibition kinetics required the use of microsomal VKORC1 with a native reductant, glutathione, that enables effective warfarin inhibition in vitro. ![]() 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. Improving the dosage management and antidotal efficacy requires mechanistic understanding. Dose control of warfarin is a major complication in anticoagulation therapy and overdose is reversed by the vitamin K antidote. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |