ArticleBlood2014
A cellular system for quantitation of vitamin K cycle activity: structure-activity effects on vitamin K antagonism by warfarin metabolites.
Article in Blood, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 40 citations in OpenAlex.
- Postoperative Rebleeding: The Sword of Damocles in Minimally Invasive Surgery for Intracerebral Hemorrhage.Research (Washington, D.C.) · 2026Review
- The Effect of Spinach (Journal of blood medicine · 2025Article
- Correlation between Metabolic Parameters and Warfarin Dose in Patients with Heart Valve Replacement of Different Genotypes.Reviews in cardiovascular medicine · 2024Article
- Assessment of gamma-glutamyl carboxylase activity in its native milieu.Methods in enzymology · 2024Article
- Vitamin K-dependent carboxylation regulates CaCell reports · 2023Article
- Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin.Frontiers in pharmacology · 2021Article
- Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation.Science (New York, N.Y.) · 2021Article
- Article
- Characterization of Warfarin Inhibition Kinetics Requires Stabilization of Intramembrane Vitamin K Epoxide Reductases.Journal of molecular biology · 2020Article
- Competitive tight-binding inhibition of VKORC1 underlies warfarin dosage variation and antidotal efficacy.Blood advances · 2020Article
- Applying Multiplex Assays to Understand Variation in Pharmacogenes.Clinical pharmacology and therapeutics · 2019Article
- Combination index of the concentration and in vivo antagonism activity of racemic warfarin and its metabolites to assess individual drug responses.Journal of thrombosis and thrombolysis · 2019Article
- VKORC1 and VKORC1L1 have distinctly different oral anticoagulant dose-response characteristics and binding sites.Blood advances · 2018Article
- Stereospecific Metabolism ofDrug metabolism and disposition: the biological fate of chemicals · 2017Article
- Warfarin and vitamin K compete for binding to Phe55 in human VKOR.Nature structural & molecular biology · 2017Article
- Functional Study of the Vitamin K Cycle Enzymes in Live Cells.Methods in enzymology · 2017Article
- Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Warfarin and other 4-hydroxycoumarins inhibit vitamin K epoxide reductase (VKOR) by depleting reduced vitamin K that is required for posttranslational modification of vitamin K-dependent clotting factors. In vitro prediction of the in vivo potency of vitamin K antagonists is complicated by the complex multicomponent nature of the vitamin K cycle. Here we describe a sensitive assay that enables quantitative analysis of γ-glutamyl carboxylation and its antagonism in live cells. We engineered a human embryonic kidney (HEK) 293-derived cell line (HEK 293-C3) to express a chimeric protein (F9CH) comprising the Gla domain of factor IX fused to the transmembrane and cytoplasmic regions of proline-rich Gla protein 2. Maximal γ-glutamyl carboxylation of F9CH required vitamin K supplementation, and was dose-dependently inhibited by racemic warfarin at a physiologically relevant concentration. Cellular γ-glutamyl carboxylation also exhibited differential VKOR inhibition by warfarin enantiomers (S > R) consistent with their in vivo potencies. We further analyzed the structure-activity relationship for inhibition of γ-glutamyl carboxylation by warfarin metabolites, observing tolerance to phenolic substitution at the C-5 and especially C-6, but not C-7 or C-8, positions on the 4-hydroxycoumarin nucleus. After correction for in vivo concentration and protein binding, 10-hydroxywarfarin and warfarin alcohols were predicted to be the most potent inhibitory metabolites in vivo.
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