The Biochemical Basis of Warfarin Therapy

  • J. W. Suttie


The necessity of a dietary nutrient to maintain normal blood coagulation function was discovered by Dam in the late 1920’s during his efforts to demonstrate the essentiality of cholesterol in the diet of the chick. He noted a hemorrhagic condition in chicks fed lipid-free diets and demonstrated that the addition of alfalfa meal or a lipid extract of alfalfa would prevent this condition. Continued study of this response in the early 1930’s by the research groups of Dam, Almquist, and Doisy led to the isolation, characterization, and synthesis of the active compound, 2-Me-3-phytyl-l, 4-naphthoquinone (phylloquinone). These early studies also demonstrated that in addition to phylloquinone or vitamin K1 in green plants, vitamin K activity was present in many bacteria as a series of menaqui-nones, 2-Me-l, 4-naphthoquinones substituted at the 3-position with an unsaturated polyisoprenoid chain. These historical aspects of the discovery of vitamin K have been adequately reviewed.1


Warfarin Therapy Quinone Reductase Carboxylation Reaction Epoxide Reductase Glutamyl Residue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J. W. Suttie, Vitamin K, in: “The Fat-soluble Vitamins,” A. T. Diplock, ed., p. 225, William Heinemann Ltd., London (1985).Google Scholar
  2. 2.
    K. P. Link, The discovery of dicumarol and its sequels. Circulation 19:97 (1959).PubMedCrossRefGoogle Scholar
  3. 3.
    J. Stenflo, P. Fernlund, W. Egan, and P. Roepstorff, Vitamin K dependent modifications of glutamic acid residues in prothrombin, Proc. Natl. Acad. Sci. USA 71:2730 (1974).PubMedCrossRefGoogle Scholar
  4. 4.
    G. L. Nelsestuen, T. H. Zytkovicz, and J. B. Howard, The mode of action of vitamin K. Identification of y-carboxyglutamic acid as a component of prothrombin, J. Biol. Chem. 249:6347 (1974).PubMedGoogle Scholar
  5. 5.
    C.T. Esmon, J. A. Sadowski, and J. W. Suttie, A new carboxylationreaction. The vitamin K-dependent incorporation of H 14 CO3 into prothrombin, J. Biol. Chem. 250:4744 (1975).PubMedGoogle Scholar
  6. 6.
    J. W. Suttie, Vitamin K-dependent carboxylase, Ann. Rev. Biochem. 54:459 (1985).PubMedCrossRefGoogle Scholar
  7. 7.
    D. H. Rich, S. R. Lehrman, M. Kawai, H. L. Goodman, and J. W. Suttie, Synthesis of peptide analogues of prothrombin precursor sequence 5–9. Substrate specificity of vitamin K dependent carboxylase, J. Med. Chem. 24:706 (1981).PubMedCrossRefGoogle Scholar
  8. 8.
    C. Vermeer, B. A. M. Soute, H. Hendrix, and M. A. G. de Boer-van den Berg, Decarboxylated bone Gla-protein as a substrate for hepatic vitamin K-dependent carboxylase, FEBS Lett. 165:16 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    G. L. Long, R. M. Belagaje, and R. T. Á. MacGillivray, Cloning and sequencing of liver cDNA coding for bovine protein C, Proc. Natl. Acad. Sci. USA 81:5653 (1984).PubMedCrossRefGoogle Scholar
  10. 10.
    L. C. Pan and P. A. Price, The propeptide of rat bone γ-carboxyglutamic acid protein shares homology with other vitamin K-dependent protein precursors, Proc. Natl. Acad. Sci. USA 82:6109 (1985).PubMedCrossRefGoogle Scholar
  11. 11.
    J. W. Suttie, J. A. Hoskins, J. Engelke, A. Hopfgartner, Bf. Ehrlich, N. U. Bang, R. M. Belagaje, B. Schoner, and G. L. Long, Vitamin K dependent carboxylase: possible role of the “propeptide” as an intracellular recognition site (γ-carboxyglutamic acid/protein C), Proc. Natl. Acad. Sci. USA (1987) in press.Google Scholar
  12. 12.
    A. E. Larson, P. A. Friedman, and J. W. Suttie, Vitamin K-dependent carboxylase: stoichiometry of carboxylation and vitamin K 2, 3-epoxide formation, J. Biol. Chem. 256:11032 (1981).PubMedGoogle Scholar
  13. 13.
    J. J. McTigue and J. W. Suttie, Vitamin Independent carboxylase: demonstration of a vitamin K- and O2-dependent exchange of 3H from 3H2O into glutamic acid residues, J. Biol. Chem. 258:12129 (1983).PubMedGoogle Scholar
  14. 14.
    D. L. Anton and P. A. Friedman, Fate of the activated y-carbon- hydrogen bond in the uncoupled vitamin K-dependent y-glutamyl carboxylation reaction, J. Biol. Chem. 258:14084 (1983).PubMedGoogle Scholar
  15. 15.
    J. Lowenthal and J. A. MacFarlane. The nature of the antagonism between vitamin K and indirect anticoagulants, J. Pharmacol. Exp. Therap. 143:273 (1964).Google Scholar
  16. 16.
    C. M. Siegfried, Purification and properties of a factor from rat liver cytosol which stimulates vitamin K epoxide reductase. Arch. Biochem. Biophys. 223:129 (1983).PubMedCrossRefGoogle Scholar
  17. 17.
    C. M. Siegfried, Solubilization of vitamin K epoxide reductase and vitamin K-dependent carboxylase from rat liver microsomes, Biochem. Biophys. Res. Commun. 83:1488 (1978).PubMedCrossRefGoogle Scholar
  18. 18.
    E. F. Bildebrandt, P. C. Preusch, J. L. Patterson, and J. W. Suttie, Solubilization and characterization of vitamin K epoxide reductase from normal and warfarin-resistant rat liver microsomes. Arch. Biochem. Biophys. 228:480 (1984).CrossRefGoogle Scholar
  19. 19.
    M. J. Fasco, L. M. Principe, W. A. Walsh, and P. A. Friedman, Warfarin inhibition of vitamin K 2, 3-epoxide reductase in rat liver microsomes. Biochemistry 22:5655 (1983).PubMedCrossRefGoogle Scholar
  20. 20.
    R. B. Silverman, Chemical model studies for the mechanism of vitamin K epoxide reductase, J. Am. Chem. Soc. 103:5939 (1981).CrossRefGoogle Scholar
  21. 21.
    P. C. Preusch and J. W. Suttie, A chemical model for the mechanism of vitarain K epoxide reductase, J. Org. Chem. 48:3301 (1983).CrossRefGoogle Scholar
  22. 22.
    R. Wallin, O. Gebhardt, and H. Prydz, NAD(P)H dehydrogenase and its role in the vitamin K (2-methyl-3-phytyl-l, 4-naphthoquinone)-dependent carboxylation reaction, Biochem. J. 169:95 (1978).PubMedGoogle Scholar
  23. 23.
    M. J. Fasco and L. M. Principe, Vitamin K1 hydroquinone formation catalyzed by DT-diaphorase, Biochem. Biophys. Res. Commun. 104:187 (1982).PubMedCrossRefGoogle Scholar
  24. 24.
    R. Wallin and L. F. Martin, Vitamin K-dependent carboxylation and vitamin K metabolism in liver. Effects of warfarin, J. Clin. Invest. 76:1879 (1985).PubMedCrossRefGoogle Scholar
  25. 25.
    R. Wall in and J. W. Suttie, Vitamin K-dependent carboxylation and vitamin K epoxidation. Evidence that the warfarin-sensitive microsomal NAD(P)H dehydrogenase reduces vitamin K in these reactions, Biochem. J. 194:983 (1981).Google Scholar
  26. 26.
    R. Wall in. Vitamin K antagonism of coumarin anticoagulation. A dehydrogenase pathway in rat liver is responsible for the antagonistic effect, Biochem. J. 236:685 (1986).Google Scholar
  27. 27.
    D. S. Whitlon, J. A. Sadowski, and J. W. Suttie, Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 17:1371 (1978).PubMedCrossRefGoogle Scholar
  28. 28.
    R. Wall in and S. Hutson, Vitamin K-dependent carboxylation. Evidence that at least two microsomal dehydrogenases reduce vitamin K1 to support carboxylation, J. Bicl. Chem. 257:1583 (1982).Google Scholar
  29. 29.
    M. J. Fasco and L. M. Principe, Vitamin IL hydroquinone formation catalyzed by a microsomal reductase system, Biochem. Biophys. Res. Commun. 97:1487 (1980).CrossRefGoogle Scholar
  30. 30.
    P. A. Sherman and E. G. Sander, Vitamin K epoxide reductase: evidence that vitamin K dihydroquinone is a product of vitamin K epoxide reduction. Biochem. Biophys. Res. Commun. 103:997 (1981).PubMedCrossRefGoogle Scholar
  31. 31.
    M. J. Fasco and L. M. Principe, R- and S-warfarin inhibition of vitamin K and vitamin K 2, 3-epoxide reductase activities in the rat, J. Biol. Chem. 257:4894 (1982).PubMedGoogle Scholar
  32. 32.
    J. T. Matschiner, R. O. Bell, J. M. Amelotti, and T. E. Knauer, Isolation and characterization of a new metabolite of phylloquinone in the rat, Biochim. Biophys. Acta 201:309 (1970).PubMedCrossRefGoogle Scholar
  33. 33.
    R. G. Bell and J. T. Matschiner, Warfarin and the inhibition of vitamin K activity by an oxide metabolite, Nature 237:32 (1972).PubMedCrossRefGoogle Scholar
  34. 34.
    A. Zimmerman and J. T. Matschiner, Biochemical basis of hereditary resistance to warfarin in the rat, Biochem. Pharmacol. 23:1033 (1974).CrossRefGoogle Scholar
  35. 35.
    E. F. Hildebrandt and J. W. Suttie, Mechanism of coumarin action: sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver, Biochemistry 21:2406 (1982).PubMedCrossRefGoogle Scholar
  36. 36.
    M. J. Fasco, E. F. Hildebrandt, and J. W. Suttie, Evidence that warfarin anticoagulant action involves two distinct reductase activities, J. Biol. Chem. 257:11210 (1982).PubMedGoogle Scholar
  37. 37.
    R. Wallin, S. D. Patrick, and J. O. Ballard, Vitamin K antagonism of coumarin intoxication in the rat, Thromb. Haemostas. (Stuttg.) 55:235 (1986).Google Scholar
  38. 38.
    P. C. Preusch and J. W. Suttie, Relationship of dithiothreitol- dependent microsomal vitamin K quinone and vitamin K epoxide reductases: inhibition of epoxide reduction by vitamin K quinone, Biochim. Biophys. Acta 798:141 (1984).PubMedCrossRefGoogle Scholar
  39. 39.
    J. J. Lee and M. J. Fasco, Metabolism of vitamin K and vitamin K 2, 3- epoxide via interaction with a common disulfide. Biochemistry 23:2246 (1984).PubMedCrossRefGoogle Scholar
  40. 40.
    R. B. Silverman, A model for a molecular mechanism of anticoagulant activity of 3-substituted 4-hydroxycoumarins, J. Am. Chem. Soc. 102:5421 (1980).CrossRefGoogle Scholar
  41. 41.
    P. A. Friedman, R. D. Rosenberg, P. V. Hauschka, and A. Fitz-James, A spectrum of partially carboxylated prothrombins in the plasmas of coumarin-treated patients. Biochim. Biophys. Acta 494:271 (1977).PubMedCrossRefGoogle Scholar
  42. 42.
    M. P. Esnouf and C. V. Prowse, The gamma-carboxy glutamic acid con- tent of human and bovine prothrombin following warfarin treatment, Biochim. Biophys. Acta 490:471 (1977).CrossRefGoogle Scholar
  43. 43.
    O. P. Maihotra, Dicoumarol-induced prothrombins, Ann. N. Y. Acad.Sci. 370:426 (1981).CrossRefGoogle Scholar
  44. 44.
    O. P. Malhotra, N. E. Nesheim, and K. G. Mann, The kinetics of activa- tion of normal and γ-carboxyglutamic acid-deficient prothrombins, J. Biol. Chem. 260:279 (1985).PubMedGoogle Scholar
  45. 45.
    R. A. Blanchard, B. C. Furie, S. F. Kruger, G. Waneck, M. J. Jorgensen, and B. Furie, Immunoassays of human prothrombin species which correlate with functional coagulant activities, J. Lab. Clin. Med. 101:242 (1983).PubMedGoogle Scholar
  46. 46.
    B. Furie, H. A. Liebman, R. A. Blanchard, M. S. Coleman, S. F. Kruger, and B. C. Furie, Comparison of the native prothrombin antigen and the prothrombin time for monitoring oral anticoagulant therapy, Blood 64:445 (1984).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1987

Authors and Affiliations

  • J. W. Suttie
    • 1
  1. 1.Department of BiochemistryUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations