VKORC1:: molecular target of coumarins

被引:107
作者
Oldenburg, J.
Watzka, M.
Rost, S.
Mueller, C. R.
机构
[1] Univ Clin Bonn, Inst Expt Haematol & Transfus Med, D-53105 Bonn, Germany
[2] Univ Wurzburg, Bioctr, Inst Human Genet, Wurzburg, Germany
关键词
genotype; haplotype; vitamin K-cycle; VKORC1; warfarin;
D O I
10.1111/j.1538-7836.2007.02549.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mu g 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.
引用
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页码:1 / 6
页数:6
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