Skip to main content
SpringerLink
Log in
Book cover

Iron Chelation Therapy pp 55–75Cite as

Intracellular and Extracellular Labile Iron Pools

  • Chapter

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 509))

Abstract

Labile forms of iron present in biological systems are defined as ionic Fe complexes that are redox active. They comprise a heterogeneous population of organic anions (phosphates and carboxylates), poly-functional ligands (i.e. chelates, siderophores and polypeptides) or surface components of membranes (e.g. phospholipid head groups) or extracellular matrix (e.g. glycans and sulfonates), which bind both forms of iron (II and III). Collectively, they define the respective labile iron pools (LIP), which can be of cellular (CLIP) or extracellular (ECLIP) nature. Operationally, those pools are characterized in terms of their propensity to engage in redox-cycling in an oxygenated environment and/or following pro-oxidant challenges. Methodologically, CLIP and ECLIP can be assessed in terms of iron reactivity and/ or the ability of the metal to undergo chelation by high affinity binding siderophores or chelators. Therapeutically, the LIPs are the immediate targets of chelators designed to reduce iron load in the entire organism, with emphasis on organs of accumulation such as the liver.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Crichton, R.R. (1991). Inorganic Biochemistry of Iron Metabolism. New York, London, Toronto, Sydney, Tokyo, Singapore, Ellis Horwood

    Google Scholar 

  2. Epaztejn, S., Kakhlon, O., Breuer, W. Gliokstein, H. and Cabantohilc, Z.I.,(1997) A fluorescence assay for the labile iron pool (LIP) of mammalian cells.Anal. Biochem. 248: 31–40.

    Article  Google Scholar 

  3. Breuer, V.W., Epstejn, S., Milgram, P. and Cabantchdc, Z.I. (1995). Transport of iron and other related metals into cells as revealed by a fluorescent probe.Am. J. Phyaiol (Cell)268: 1354–1361.

    Google Scholar 

  4. Breuer, W., Epstejn, S, and Cabantchik, Z.I. (1995). Iron acquired from transfenin by K562 cells is delivered into a oytoplasmic pool of chelatable iron(II).J. Biol. Chem. 270: 24209–24215

    Article  CAS  Google Scholar 

  5. Jacobs, A. (1977) An intracellular transit iron pool.Blood50: 4331–4336.

    Google Scholar 

  6. Kozlov, A.V., Yegorov, D.Y., Vladimirov, Y.A. and Azizova,O.A. (1992). Intracellular iton in liver tissue and liver homegenatc-tudies with electron paramagnetic resonance onthe formation of paramagnetic complexes with desfecal and nitric oxide.Free Rad BioL Med13: 9–16.

    Article  CAS  Google Scholar 

  7. Rothman, R. J., Serroni, A. and Farber, J. L. (1992). Cellular pool of transient ferric iron, ohelatable by deferoxamine and distinct front Ft, that is involved in oxidative cell injury.MoL PharmacoL42: 703–710

    CAS  Google Scholar 

  8. Eisenstein, RD. (2000) Iron regulator proteins and the molecular control of mammalian iron metabolism Annu Rev.Nutr.20:627–62

    Google Scholar 

  9. Aisen P, Wessling-Resnick M, Leibold EA. Iron metabolism (1999). Cues Opin Chem Bio13:200–6

    Google Scholar 

  10. Hershko H, Graham G, Bates GW, Rachmilewitz E: Nonspecific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Brit. J. Haematol. 1978; 40: 255–263.

    Article  CAS  Google Scholar 

  11. Graham G, Bates GW, Rachmilewitz EA, Hershko C: Nonspecific serum iron in thalassemia: quantitation and chemical reactivity. Am. J. Hematol. 1979; 6:207–217.

    Article  CAS  Google Scholar 

  12. Porter JB, Abeysinghe RD, Marshall L, Hider RC, Singh S: Kinetios of removal and reappearance of non-transfe inbound pluma iron with deferoxamine therapy. Blood 1996; 88:705–13.

    CAS  Google Scholar 

  13. Batey RG, Lai Chung Fong P, Shamir S, Sherlock S: A non-transfer in-bound serum iron in idiopathic hemochromatosis. Dig Dis Sci. 1980; 25:340–6.

    Article  CAS  Google Scholar 

  14. Aruoma OI, Bomford A, Polson RJ, Halliwell B: Nontransfenin-bound iron in plasma from hemochromatosis patients: effect of phlebotomy therapy. Blood 1988; 72:1416–9.

    CAS  Google Scholar 

  15. Loral D, Gosriwatana I, Guyader D, Porter J, Brissot P, Hider RC: Determination of non-tranaferrin-bound iron in genetic hemochromatosis using a new HPLC-baud method. J Hepatol. 2000; 32:727–33.

    Article  Google Scholar 

  16. Brauer W, Hershko C, Cabantchik ZL (2000) The importanoe of non#anaferrin iron in disorder of iron metabolism. Transfusion Soi. 2000; 23: 185–92.

    Article  Google Scholar 

  17. Gosriwatana 1, 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; 273:212–20.

    Article  CAS  Google Scholar 

  18. Breuer W, Ronson A, Slotki IN, Abramov A, Hershko C, Cabantchik ZI: The assessment of serum nontransferrinbound iron in ohelation therapy and iron supplementation. Blood. 2000; 95:2975–82.

    CAS  Google Scholar 

  19. Breuer W, Eimers, MJJ, Pootrakul P, Abramov A, Hershko C, Cabantchik ZI: Desferrioxamine-dtdatabk iron (DCI), a component durum non-transferrin bound iron (NTBI) used for assessing ahelation therapy. Blood. 97:792–8.

    Google Scholar 

  20. Halliwell B, Gutteridge JM: Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 1990; 186:1–85.

    Article  CAS  Google Scholar 

  21. Wright TL, Brissot P, Ma WL, Weisiger RA: Characterization of non-transferrin-bound iron clearance by rat liver. J Bid Chem. 1986; 261:10909–14.

    CAS  Google Scholar 

  22. Kaplan J, Jordan I, Sturrock A: Regulation of the transferrin-independent iron transport system in cultured cells. J Biol Chem. 1991; 266:2997–3004

    CAS  Google Scholar 

  23. Shalev O, Repka T, Goldfarb A, Grinberg L, Abrahamov A, Oliviori NF, Raohmilewitz EA, Hebbel RP.1995. Deferiprone (Ll) chelates pathologic iron deposits from membranes of intact thalassanic and sickle red blood cells both in vitro and in vivo. Blood. 86:2008–13

    CAS  Google Scholar 

  24. Cabantohik ZI, Breuer W, Slotki I, Beaumont C. (2001) Development and application of novel fluorescent assays for probing labile iron pools in biological systems. In: Badman DG, Bergeron RJ, Britt:sham GM, eds.Iron Chelators: New development strategies. Ponto Veda’, FL: The Saratoga Group; 2000:353–383.

    Google Scholar 

  25. Tsien, R. Y. (1989) Fluorescent probes of cell signaling.Ann.Rev. Neuroaci. 12: 227–53

    Article  CAS  Google Scholar 

  26. Ramachandram, B. and A. Samanta, A.1998. How important is the quenching influence of the transition metal ions in the design of fluorescent PET sensors? Chemical Physics Letters 290: 9–16

    Article  CAS  Google Scholar 

  27. Lytton, S.J., Mesta, B., Libman, J., Shanzer, A. and Cabentchik, Z.I.. (1992). Monitoring of iron(III) removal from biological sources using a novel fluorescent siderophore.Anal. Biochem. 205: 326–333

    Article  CAS  Google Scholar 

  28. Worts, M.ILV., Hofstraat, J.W., Gauls, F.A.J., and Verhoeven, J.W. 1997 Fluorescein and eosin as sensitizing ahromophores in near-infrared luminescent ytterbium(III), neodymium(III) and Terbium(III) chelates Chemical Physics Letters 276:196–201

    Google Scholar 

  29. Breuer W and Cabantohik ZI. (2001) A fluorescence based one-step assay for serum non-tranaferrin bound iron (NTBI).Anal. Biochem. (submitted).

    Google Scholar 

  30. Ramachandram, B. and A. Samanta, A.1998. Transition Metal Ion Induced fluorescence Enhancement of 4-(N, NDimethylethylenediamino)- 7- nitrobenz- 2- oxa- 1,3- diazoleJ. Phys. Chem. 102: 10579–10587.

    CAS  Google Scholar 

  31. Petrat F, Rauen U, de Groot H. 1999. Determination of the chelatable iron pool of isolated rat hepatocytes by digital fluorescence microscopy using the fluorescent probe,phen green SK.Hepatology. 29:1171–9.

    Google Scholar 

  32. Thomas F, Serratrice G, Beguin C, Aman ES, Pierre JL, Fontecave M, Laulhere JP. 1999 Calcein as a fluorescent probe for ferric iron. Application to iron nutrition in plant cells.J Biol Chem. 274:13375–83

    CAS  Google Scholar 

  33. Staubli A, Boelsterli UA 1998.The labile iron pool in hepatocytes: prooxidant-induced increase in free iron precedes oxidative cell injury Am J Physiol. 274:G1031–7.

    Google Scholar 

  34. Epsztejn, S. Picard. V, Breuer, W.V., Glickstein, H. Slotki, I.N., Beaumont C. and Cabantchik, Z.I. (1999). Functional consequences of H-ferritin over-expression in transfected cells.Blood94:3593–3603..

    CAS  Google Scholar 

  35. Richardson, D.R. and Ponka, P. 1997 The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.Biochim. Beophys Acta. 1331: 1.40

    Google Scholar 

  36. Cabantchik, Z.I., Milgram, P., Glikhstkin, H. and Breuer, W., (1995) A method for assessing iron chelation in membrane model systems and in living mammalian cells.AnaL Biochem. 233: 221–227.

    Article  Google Scholar 

  37. Zanninelli, G., Brissot, P., Hider, RR., Konijn, A.P., Shama, A. and Cabantchílc, Z.L (1997). Chelation and mobilization of cellular iron by different classa of iron chelaton. MoLPharmacoL51: 842–852.

    CAS  Google Scholar 

  38. Bevilacqua, M.A., Faniello, M.C., Quaresima, B., Tiano, M.T., Giuliano, P., Feliciello, A., Avvedimento, V.E., Cimino, F. & Costanzo, F. (1997) A oommon mechanism underlying the E1A agression and the °AMP stimulation °f the H fa kin transcription.JBioLChem272: 20736–20741

    CAS  Google Scholar 

  39. Bevilaoqua, M A, Faniello, M.C, Russo, T., Cimino, F. & Castanzo, F. (1998) P/CAF/p300 complex binds the promoter for the heavy subunit of ferritin and contributes to ib tissue-specific expression.BiochemJ335: 521–525

    Google Scholar 

  40. Fuhrmann, G., Rosenberger, G., Causch, M., Klein, N., Hofmann, J. & Krupp G. (1999) The MYC dualism in growth and death.MutatRes. 437: 205–217

    CAS  Google Scholar 

  41. Tsuji, Y., Kwak, E., Seiko, T., Tati, S.V. & Tati, F.M. (1993) Preferential repression of the H subunit of ferritin by adawovirus E1 A in NIH-3T3 mouse fibroblasts.J.BioLChem. 268: 7270–7275

    CAS  Google Scholar 

  42. Tsuji, Y., Akebi, N., Lam, T.K., Nakabeppu, Y., Tati, S.V. & Tord, F.M. (1995) FER-1, an enhancer of the ferritin H gare and a target of El A-mediated transcriptional repression.MoLCell BioL15: 5152–5164

    CAS  Google Scholar 

  43. Tsuji, Y., Moran, E., Torii, S.V. & Torti, F.M. (1999) Transcriptional regulation of the mouse faritin H gene. Involvement of p300/CBP adaptor proteins in FER-1 enhancer activity.JBioLChem274: 7501–7507

    CAS  Google Scholar 

  44. Wu, K.J, Polack, A&Dalla Favors, R. (1999) Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by o-MYC.Science283: 676–679

    Article  Google Scholar 

  45. Pinero, D.J., Hu, J., Cook, B.M., Scaduto, RC. & Connor, J.R. (2000) Interleukin-lbda increases binding of the iron regulatory protein and the synthesis of ferritin by increasing the labile iron pool.Biochim.BiophysActa1497: 279288

    Google Scholar 

  46. Picard, V., Renaudie, F., Porcher, C., Henke, M.W., Grandchamp, B. & Beaumont, C. (1996) Ove expression tithe ferritin H subunit in cultured erythroid cells changes the intracellular iron distribution.Blood87: 2057–2064

    CAS  Google Scholar 

  47. Picard, V., Epztejn, S., Santambrogio, P., Cabantchik, Z.I. & Beaumont, C. (1998) Roleoffaritin in the control of the labile iron pod in murine erythroleukemia cells.J.BioLChem. 273:15382–15386

    CAS  Google Scholar 

  48. Cozzi, A., Corsi, B., Levi S, Santambrogio, P., Albertini, A. & Araio, P. (2000) Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: in vivo role of ferritin ferroxidase aotivity.J.BioLChem. 275: 2512225129

    Google Scholar 

  49. Kakhlon, A., Gruenbeum, Y. & Cabantchik, Z.I (2001) Repression of ferritin expression increases the labile iron pool, oxidative stress, and short term growth of human erythroleukemia oells.Blood97: 2863–2871.

    Article  CAS  Google Scholar 

  50. Kakhlon O, Gruenbaum Y, Cabantohik ZI. (2001) Repression of the heavy ferritin chain increases the labile iron pool of human K562 cells.Biochem J. 2001 Jun 1;356 (Pt 2):311–316.

    Article  CAS  Google Scholar 

  51. Tilbrook, G.S. and Hider, R.C. Iron chelaten for clinical use. In: Sigel, A. and Sigel, IL, eds.Metal Ions in Biological System’s: Iron Transport and Storage in Microorganisms Planer and Animals. 1998;Vol. 35:691–730. Marcel Dekker, New Yak.

    Google Scholar 

  52. Pollack S, Aisen P, Lasky FD, Vanderhoff G. (1976) Chelate mediated transfer of iron from transferrin to desfenicxamine.BrJ Haematol. 34:231–5.

    Article  CAS  Google Scholar 

  53. Pollack, S., Vanderhoff G. and Lasky, F. (1977) Iron removal from transferrin-an experimental study.Biochim. Brophy:. Acta497: 481–487.

    CAS  Google Scholar 

  54. Kontoghiorghes, G.J. (1995) New concepts of iron and aluminium °halation therapy with oral LI (Deferiprone) and other chelators.Analyst120:845–851.

    Article  CAS  Google Scholar 

  55. Aisen P, Leibman A, Zweier J. (1978) Stoichiometric and site characteristics of the binding of iron to human transferrin.JBiol Chem. 253:1930–7.

    CAS  Google Scholar 

  56. Evans, KW., Sharma, M., Ogwang, W., Patel, K.J., Bartlett, A.N. and Kontoghiorghes. (1992) The effect of alphaketo hydropyridine ohelakes on transfe ria saturation in vitro and in vivo.Drugs ofToday;28 (Suppl. A):19–23.

    CAS  Google Scholar 

  57. Wang WC, Ahmed N, Hanna M. J.Pediatr(1986) 108:552–7 Nor-tranafarm-bound iron in long-term transfusion in children with congenital anemias.

    Google Scholar 

  58. Ahmed NK. Hanna M. Wang W. (1986) Nontransferrin-bound serum iron in thalassemia and sickle cell patients.Intern. J. Biochem. 18:953–956.

    Article  Google Scholar 

  59. Araujo A, Kosaryan M, MaDDowell A, Wickens D, Puri S, Wonke B, Hoñbrand AV. (1996) A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload.BrJHaematol;93:835–7.

    Article  CAS  Google Scholar 

  60. al-Refaie FN., Wickens, DG., Wonke ,B. Kontoghiorghes GJ. and Hofbrand AV. (1992). Serum non-4ansfe inbound iron in beta4halassaemia major patients treated with desferrioxamine and L1.Brit. J. Haematol. 82:431–436.

    Article  CAS  Google Scholar 

  61. Wonke, B., Wright, C. and Hofbrand, kV. (1998) Combined therapy with defertprone and desferrioxamine.Br. J. Haematol. 103:361–4.

    Article  CAS  Google Scholar 

  62. Grady, R W., Berdoukas, V.A., Rachmilewitz, E.A. and Giardina, P.I. Combining deferiprone and desferrioxamine to optimize chdation. 10aInternational Conference on Oral Chelators, Limassol, Cyprus, Mar.22–26, 2000.

    Google Scholar 

  63. Grady, kW. and Giardina, P.J. Iron Chelation: Rationale for combination therapy. In: Badman, D.G., Bergeron, R.J. and Brittenham, G.M. eds.Iron Chelators: New development strategies. 2000; 293–310. The Saratoga Group, Ponte Ved., FL.

    Google Scholar 

  64. Singh, S., Hider, R.C. and Porter, J.B. (1990) A direct method for quantification of non-transferrin-bound iron.Anal Biochem. 186:320–323.

    Article  CAS  Google Scholar 

  65. Evans, PJ, Halliwell, B. (1994). Measurement of iron and copper in biological systems: bleomycin and copperphenanthroline assays.Meth. Enzymol. 233:82–89.

    Article  CAS  Google Scholar 

  66. Scheiber B, Goldenberg H. (1998). The surface of rat hepatocytes can transfer iron from stable ohelates to external acceptors.Hepatology. 27:1075–80.

    Article  CAS  Google Scholar 

  67. long TC, Deugnier Y, Halliday JW, Powell LW, Brissot P. (1997). Ultrastructural sequences during liver iron overload in genetic hemochromatosis.J. Hepatol. 27:628–38.

    Article  Google Scholar 

  68. Simpson RJ, Dee nmamode J, McKie AT, Raja KB, Salisbury JR, Iona TC, Peters TJ. (1997): Time-course of iron overload and biochemical, histopathological and ultrastructural evidence of pancreatic damage inhypotransferrina micmice. Clin. Sct (Cokh). 93:453–62.

    CAS  Google Scholar 

  69. Moura E, Noardc me er MA, Verhoeven N, Verheul AF, Marx JI. (1998). Iron release from human monocytes after e ythrophagocytosis in vitro: an investigation in normal subjects and hereditary hemochromatosis patients.Blood. 92:2511–9.

    CAS  Google Scholar 

  70. Grootveld, M, Bell, J.D., Halliwell, B., Aruoma, O.I., Bomfard, A. and Sadler, P.J. (1989) Non4ransferrin bound iron in plasma or serum from patients with idiopathic hemochromatosis.J. Biol. Chem. 264:4417–22.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, 91904, Israel

    Z. Ioav Cabantchik, Or Kakhlon, Silvina Epsztejn, Giulianna Zanninelli & William Breuer

Authors
  1. Z. Ioav Cabantchik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Or Kakhlon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvina Epsztejn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giulianna Zanninelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William Breuer
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Hebrew University School of Medicine, Jerusalem, Israel

    Chaim Hershko

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Kluwer Academic/Plenum Publishers, New York

About this chapter

Cite this chapter

Cabantchik, Z.I., Kakhlon, O., Epsztejn, S., Zanninelli, G., Breuer, W. (2002). Intracellular and Extracellular Labile Iron Pools. In: Hershko, C. (eds) Iron Chelation Therapy. Advances in Experimental Medicine and Biology, vol 509. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0593-8_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0593-8_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-306-46785-1

  • Online ISBN: 978-1-4615-0593-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation