VKORC1:: molecular target of coumarins

被引:108
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
收藏
页码:1 / 6
页数:6
相关论文
共 41 条
[31]   Vitamin K epoxide reductase significantly improves carboxylation in a cell line overexpressing factor X [J].
Sun, YM ;
Jin, DY ;
Camire, RM ;
Stafford, DW .
BLOOD, 2005, 106 (12) :3811-3815
[32]   A warfarin-dosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P4502C9 [J].
Tham, Lai-San ;
Goh, Boon-Cher ;
Nafziger, Anne ;
Guo, Jia-Yi ;
Wang, Ling-Zhi ;
Soong, Richie ;
Lee, Soo-Chin .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2006, 80 (04) :346-355
[33]   Membrane topology mapping of vitamin K epoxide reductase by in vitro translation/cotranslocation [J].
Tie, JK ;
Nicchitta, C ;
von Heijne, G ;
Stafford, DW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (16) :16410-16416
[34]   Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin [J].
Vecsler, M ;
Loebstein, R ;
Almog, S ;
Kurnik, D ;
Goldman, B ;
Halkin, H ;
Gak, E .
THROMBOSIS AND HAEMOSTASIS, 2006, 95 (02) :205-211
[35]   The risk of bleeding complications in patients with cytochrome P450CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon [J].
Visser, LE ;
van Schaik, RHN ;
van Vliet, M ;
Trienekens, PH ;
De Smet, PAGM ;
Vulto, AG ;
Hofman, A ;
van Duijn, CM ;
Stricker, BHC .
THROMBOSIS AND HAEMOSTASIS, 2004, 92 (01) :61-66
[36]   Association of warfarin dose with genes involved in its action and metabolism [J].
Wadelius, Mia ;
Chen, Leslie Y. ;
Eriksson, Niclas ;
Bumpstead, Suzannah ;
Ghori, Jilur ;
Wadelius, Claes ;
Bentley, David ;
McGinnis, Ralph ;
Deloukas, Panos .
HUMAN GENETICS, 2007, 121 (01) :23-34
[37]   Increased production of functional recombinant human clotting factor IX by baby hamster kidney cells engineered to overexpress VKORC1, the vitamin K 2,3-epoxide-reducing enzyme of the vitamin K cycle [J].
Wajih, N ;
Hutson, SM ;
Owen, J ;
Wallin, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (36) :31603-31607
[38]   Engineering of a recombinant vitamin K-dependent γ-carboxylation system with enhanced γ-carboxyglutamic acid forming capacity -: Evidence for a functional CXXC redox center in the system [J].
Wajih, N ;
Sane, DC ;
Hutson, SM ;
Wallin, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (11) :10540-10547
[39]   Disulfide-dependent protein folding is linked to operation of the vitamin K cycle in the endoplasmic reticulum -: A protein disulfide isomerase-VKORC1 redox enzyme complex appears to be responsible for vitamin K1 2,3-epoxide reduction [J].
Wajih, Nadeem ;
Hutson, Susan M. ;
Wallin, Reidar .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (04) :2626-2635
[40]   MAJOR GENE CONTROLLING WARFARIN-RESISTANCE IN HOUSE MOUSE [J].
WALLACE, ME ;
MACSWINEY, FJ .
JOURNAL OF HYGIENE, 1976, 76 (02) :173-181