Translational Research
Volume 156, Issue 2 , Pages 55-67 , August 2010

Mechanisms for the shuttling of plasma non-transferrin-bound iron (NTBI) onto deferoxamine by deferiprone

  • Patricia Evans

      Affiliations

    • Department of Hematology, University College London Medical School, London, United Kingdom
    • Corresponding Author InformationReprint requests: Patricia Evans, Department of Hematology, University College London, The Cancer Institute, Paul O'Gorman Building, Huntley Street, London WC1E 6BT, United Kingdom
    • ,
  • Reem Kayyali

      Affiliations

    • School of Pharmacy and Chemistry, Kingston University, Kingston, United Kingdom
    • ,
  • Robert C. Hider

      Affiliations

    • The Department of Pharmacy, King's College London, London, United Kingdom
    • ,
  • John Eccleston

      Affiliations

    • The National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom
    • ,
  • John B. Porter

      Affiliations

    • Department of Hematology, University College London Medical School, London, United Kingdom

Received 24 March 2010 ,Revised 29 April 2010 ,Accepted 1 May 2010.

References 

  1. Hershko C, Graham G, Bates GW, Rachmilewitz EA. Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br J Haematol. 1978;40:255–263
  2. Oudit GY, Sun H, Trivieri MG, et al. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med. 2003;9:1187–1194
  3. Porter JB, Rafique R, Srichairatanakool S, et al. Recent insights into interactions of deferoxamine with cellular and plasma iron pools: implications for clinical use. Ann N Y Acad Sci. 2005;1054:155–168
  4. Porter JB, Abeysinghe RD, Marshall L, Hider RC, Singh S. Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy. Blood. 1996;88:705–713
  5. Breuer W, Ermers MJ, Pootrakul P, Abramov A, Hershko C, Cabantchik ZI. Desferrioxamine-chelatable iron, a component of serum non-transferrin- bound iron, used for assessing chelation therapy. Blood. 2001;97:792–798
  6. Evans RW, Rafique R, Zarea A, et al. Nature of non-transferrin-bound iron: studies on iron citrate complexes and thalassemic sera. J Biol Inorg Chem. 2008;13:57–74
  7. Silva AM, Kong X, Parkin MC, Cammack R, Hider RC. Iron(III) citrate speciation in aqueous solution. Dalton Trans. 2009;8616–8625
  8. Silva AM, Hider RC. Influence of non-enzymatic post-translation modifications on the ability of human serum albumin to bind iron. Implications for non-transferrin-bound iron speciation. Biochim Biophys Acta. 2009;1794:1449–1458
  9. al-Refaie FN, Wickens DG, Wonke B, Kontoghiorghes GJ, Hoffbrand AV. Serum non-transferrin-bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1. Br J Haematol. 1992;82:431–436
  10. Pootrakul P, Sirankapracha P, Sankote J, et al. Clinical trial of deferiprone iron chelation therapy in beta-thalassaemia/haemoglobin E patients in Thailand. Br J Haematol. 2003;122:305–310
  11. Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol. 2005;18:277–287
  12. Zanninelli G, Breuer W, Cabantchik ZI. Daily labile plasma iron as an indicator of chelator activity in Thalassaemia major patients. Br J Haematol. 2009;147:744–751
  13. Walter PB, Macklin EA, Porter J, et al. Inflammation and oxidant-stress in {beta}-thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial. Haematologica. 2008;93:817–825
  14. May P, Williams D. Synergistic chelation therapy or mixed ligand complexes for plutonium or cadmium poisoning. Nature. 1979;278:581
  15. Pollack S, Aisen P, Lasky FD, Vanderhoff G. Chelate mediated transfer of iron from transferrin to desferrioxamine. Br J Haematol. 1976;34:231–235
  16. Jackson GE, May PM, Williams DR. The action of chelating agents in the removal of copper from ceruloplasmin: an in vitro study. FEBS Lett. 1978;90:173–177
  17. Schubert J, Derr SK. Mixed ligand chelate therapy for plutonium and cadmium poisoning. Nature. 1978;275:311–313
  18. Aydinok Y, Ulger Z, Nart D, et al. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major. Haematologica. 2007;92:1599–1606
  19. Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007;115:1876–1884
  20. Giardina PJ, Grady RW. Chelation therapy in beta-thalassemia: an optimistic update. Semin Hematol. 2001;38:360–366
  21. Grady RW, Giardina PJ. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med. 1998;339:1712–1713author reply 3–4
  22. Martell A. The design and synthesis of chelating agents. Amsterdam, The Netherlands: Elsevier North Holland Inc; 1981;
  23. Ihnat P, Vennerstrom J, Robinson D. Solution equilibria of deferoxamine amides. J Pharm Sci. 2002;91:1733–1741
  24. Motekaitis R, Martell A. Stabilities of the iron(III) chelates of 1,2-dimethyl-3-hydroxy-4-pyridinone and related ligands. Inorganica Chim Acta. 1991;183:71–80
  25. Link G, Konijn AM, Breuer W, Cabantchik ZI, Hershko C. Exploring the “iron shuttle” hypothesis in chelation therapy: effects of combined deferoxamine and deferiprone treatment in hypertransfused rats with labeled iron stores and in iron-loaded rat heart cells in culture. J Lab Clin Med. 2001;138:130–138
  26. Srichairatanakool S, Kemp P, Porter JB. Evidence for “shuttle” effect of NTBI onto desferrioxamine in thalassaemic plasma in the presence of NTA. In: International Symposium: Iron in Biology and Medicine; 1997, St. Malo, France. p. 210.
  27. Esposito BP, Breuer W, Sirankapracha P, Pootrakul P, Hershko C, Cabantchik ZI. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood. 2003;102:2670–2677
  28. Dobbin PS, Hider RC, Hall AD, et al. Synthesis, physicochemical properties, and biological evaluation of N- substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: orally active iron chelators with clinical potential. J Med Chem. 1993;36:2448–2458
  29. Alderighi L, Gans P, Ienco A, Peters D, Sabatini A, Vacca A. Hyperquad simulation and speciation (hyss): a utility program for the investigation of equilibria involving soluble and partially soluble species. Coord Chem Rev. 1999;184:311–318
  30. Singh S, Hider RC, Porter JB. A direct method for quantification of non-transferrin-bound iron. Anal Biochem. 1990;186:320–323
  31. Gosriwatana I, Loreal O, Lu S, Brissot P, Porter J, Hider RC. Quantification of non-transferrin-bound iron in the presence of unsaturated transferrin. Anal Biochem. 1999;273:212–220
  32. Grootveld M, Bell JD, Halliwell B, Aruoma OI, Bomford A, Sadler PJ. Non-transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy. J Biol Chem. 1989;264:4417–4422
  33. Porter JB. Deferoxamine pharmacokinetics. Semin Hematol. 2001;38:63–68
  34. al-Refaie FN, Sheppard LN, Nortey P, Wonke B, Hoffbrand AV. Pharmacokinetics of the oral iron chelator deferiprone (L1) in patients with iron overload. Br J Haematol. 1995;89:403–408
  35. Kontoghiorghes GJ, Goddard JG, Bartlett AN, Sheppard L. Pharmacokinetic studies in humans with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Clin Pharmacol. 1990;48:255–261
  36. Kushner JP, Porter JP, Olivieri NF. Secondary iron overload. Hematology Am Soc Hematol Educ Program. 2001;47–61
  37. Faller B, Nick H. Kinetics and mechanism of iron(III) removal from citrate by desferrioxamine B and 3-hydroxy-1,2-dimethyl-4-pyridone. J Am Chem Soc. 1994;116:3860–3865
  38. Lentner CE. Geigy Scientific Tables Basle, Switzerland: Ciba-Geigy Limited; 1981;
  39. Cooper CE, Lynagh GR, Hoyes KP, Hider RC, Cammack R, Porter JB. The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J Biol Chem. 1996;271:20291–20299
  40. Hider R. Nature of non-transferrin-bound iron. Eur J Clin Invest. 2002;32:S50–S54

 This article is dedicated to the memory of the late Dr John Eccleston.

 Supported by the following grants from NIH (Bethesda, MD): DK57645-01 and IR01DK55462-02.

PII: S1931-5244(10)00092-7

doi: 10.1016/j.trsl.2010.05.002

Translational Research
Volume 156, Issue 2 , Pages 55-67 , August 2010

Article Tools

* Image Usage & Resolution