Related Experiment Video
Updated: Mar 31, 2026

Author Spotlight: Genetic Profiling for Fluorouracil Response in Gastric Cancer
Published on: May 10, 2024
Warfarin resistance associated with genetic polymorphism of VKORC1: linking clinical response to molecular mechanism
Benjamin C Lewis1, Pramod C Nair, Subash S Heran
1aDepartment of Clinical Pharmacology bFlinders Centre for Innovation in Cancer, Flinders University School of Medicine cDepartment of Respiratory Medicine, Flinders Medical Centre dDiscipline of Pharmacology, University of Adelaide School of Medical Sciences, Adelaide, South Australia, Australia.
Abstract:
The variable response to warfarin treatment often has a genetic basis. A protein homology model of human vitamin K epoxide reductase, subunit 1 (VKORC1), was generated to elucidate the mechanism of warfarin resistance observed in a patient with the Val66Met mutation. The VKORC1 homology model comprises four transmembrane (TM) helical domains and a half helical lid domain. Cys132 and Cys135, located in the N-terminal end of TM-4, are linked through a disulfide bond. Two distinct binding sites for warfarin were identified. Site-1, which binds vitamin K epoxide (KO) in a catalytically favorable orientation, shows higher affinity for S-warfarin compared with R-warfarin. Site-2, positioned in the domain occupied by the hydrophobic tail of KO, binds both warfarin enantiomers with similar affinity. Displacement of Arg37 occurs in the Val66Met mutant, blocking access of warfarin (but not KO) to Site-1, consistent with clinical observation of warfarin resistance.
More Related Videos
Related Concept Videos
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Pharmacogenetics of Drug Metabolism: Overview
Principles of Pharmacogenetics: Types of Genetic Variants
Anticoagulant Drugs: Vitamin K Antagonists and Direct Oral Anticoagulants
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
Pharmacogenomics: Identification of New Drug Targets
Drug toxicity: Idiosyncratic Reactions

