VKORC1: molecular target of coumarins
The genetic diagnosis of a single family with combined vitamin K‐dependent clotting factor deficiency (VKCFD2, OMIM #607473) finally led to the identification and molecular characterization of vitamin K epoxide reductase (VKORC1). VKORC1 is the key enzyme of the vitamin K cycle and the molecular tar...
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Veröffentlicht in: | Journal of thrombosis and haemostasis 2007-07, Vol.5 (s1), p.1-6 |
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Sprache: | eng |
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Zusammenfassung: | The genetic diagnosis of a single family with combined vitamin K‐dependent clotting factor deficiency (VKCFD2, OMIM #607473) finally led to the identification and molecular characterization of vitamin K epoxide reductase (VKORC1). VKORC1 is the key enzyme of the vitamin K cycle and the molecular target of coumarins, which represent the most commonly prescribed drugs for therapy and prevention of thromboembolic conditions. However, coumarins are known to have a narrow therapeutic window and a considerable risk of bleeding complications caused by a broad variation of intra‐ and inter‐individual drug requirement. Now, 3 years after its identification, VKORC1 has greatly improved our understanding of the vitamin K cycle and has led to the translation of basic research into clinical practise in at least three directions: (i) Mutations within VKORC1 have been shown to cause a coumarin‐resistant phenotype and a single SNP (rs9923231) within the VKORC1 promoter region has been identified as the major pharmacodynamic determinant of coumarin dose. Together with the previously described CYP2C9 variants and other dose‐influencing factors, such as age, gender and weight, individualized dosing algorithms have become available. (ii) Preliminary studies indicate that concomitant application of low‐dose vitamin K (80–100 μg day−1) and warfarin significantly improves INR stability and time of INR within the therapeutic range. (iii) Co‐expression studies of FIX and FX with VKORC1 have shown that VKOR activity is the rate‐limiting step in the synthesis of biologically active vitamin K‐dependent factors. Thus, co‐expression of VKORC1 leads to a more efficient production of recombinant vitamin K‐dependent coagulation factors such as FIX and FVII. This could improve production of recombinant factor concentrates in the future. |
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ISSN: | 1538-7933 1538-7836 1538-7836 |
DOI: | 10.1111/j.1538-7836.2007.02549.x |