Skip to main content
SpringerLink
Log in

The Role of Iron in Alcohol-Mediated Hepatocarcinogenesis

  • Conference paper
  • First Online:
Biological Basis of Alcohol-Induced Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 815))

Abstract

Alcoholic liver disease (ALD) is the major liver disease in the developed world and characterized by hepatic iron overload in ca. 50 % of all patients. This iron overload is an independent factor of disease progression, hepatocellular carcinoma and it determines survival. Since simple phlebotomy does not allow the efficient removal of excess iron in ALD, a better understanding of the underlying mechanisms is urgently needed to identify novel targeted treatment strategies. This review summarizes the present knowledge on iron overload in patients with ALD.

Although multiple sides of the cellular and systemic iron homeostasis may be affected during alcohol consumption, most studies have focused on potential hepatic causes. However, it should not be overlooked that more than 90 % of the major iron pool, the hemoglobin-associated iron, is efficiently recycled within the human body and it is also strongly affected by alcohol. The few available studies suggest various molecular mechanisms that involve iron regulatory protein (IRP1), transferrin receptor 1 (TfR1), and the systemic iron master switch hepcidin, but not classical mutations of the HFE gene. Notably, reactive oxygen species (ROS), namely, hydrogen peroxide (H2O2), are powerful modulators of these iron-steering proteins. For instance, depending on the level, H2O2 may both strongly suppress and induce the expression of hepcidin that could partly explain the anemia and iron overload observed in these patients. More studies with appropriate ROS models such as the novel GOX/CAT system are required to unravel the mechanisms of iron overload in ALD to consequently identify molecular-targeted therapies in the future.

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

Access this chapter

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 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

Institutional subscriptions

Abbreviations

ALAS:

Aminolevulinic acid synthase

ALD:

Alcoholic liver disease

DMT1:

Divalent metal transporter 1

FP:

Ferroportin

GGT:

Gamma-glutamyltransferase

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HFE:

Gene that is mutated in hereditary hemochromatosis

HH:

Hereditary hemochromatosis

HO-1:

Heme oxygenase 1

IRE:

Iron-responsive element

IRP:

Iron regulatory protein

ISC:

Iron sulfur cluster

MPO:

Myeloperoxidase

NO:

Nitrogen oxide

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SOCS3:

Suppressor of cytokine signaling 3

STAT3:

Signal transducer and activator of transcription 3

TfR:

Transferrin receptor

TNF:

α Tumor necrosis factor α

YLL:

Years of life loss

References

  1. Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7:599–612

    Article  CAS  PubMed  Google Scholar 

  2. Seitz HK, Mueller S (2011) Ethanol metabolism and its consequences. In: Anzenbacher P, Zanger U (eds) Metabolism of Drugs and Xenobiotics. Weinheim, Wiley

    Google Scholar 

  3. Mueller S, Millonig G, Seitz HK, Waite GN (2012) Chemiluminescence detection of hydrogen peroxide. In: Schipper H, Pantopoulos K (eds) Principles of Free Radical Biomedicine. Nova Publishers, New York

    Google Scholar 

  4. Mueller S, Millonig G, Seitz HK (2009) Alcoholic liver disease and hepatitis C: a frequently underestimated combination. World J Gastroenterol 15:3462–3471

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Cochrane J, Chen H, Conigrave KM, Hao W (2003) Alcohol use in China. Alcohol Alcohol 38:537–542

    Article  PubMed  Google Scholar 

  6. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL et al (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2095–2128

    Article  PubMed  Google Scholar 

  7. Powell LW (1975) The role of alcoholism in hepatic storage disease. In: Seixas FA, Williams K, Seggleston S (eds) Medical consequences of alcoholism. New York Academy of Sciences, New York

    Google Scholar 

  8. Finch SC, Finch CA (1955) Idiopathic hemochromatosis, an iron storage disease. A iron metabolism in hemochromatosis. Medicine (Baltimore) 34:381–430

    Article  CAS  Google Scholar 

  9. Sheldon JH (1935) Haemochromatosis. Oxford University Press, London

    Google Scholar 

  10. Bell ET (1955) The relation of portal cirrhosis to hemochromatosis and to diabetes mellitus. Diabetes 4:435–446

    CAS  PubMed  Google Scholar 

  11. Conrad ME, Berman A Jr, Crosby WH (1962) Iron kinetics in laennec’s cirrhosis. Gastroenterology 43:385–390

    CAS  PubMed  Google Scholar 

  12. Tavill AS, Qadri AM (2004) Alcohol and iron. Semin Liver Dis 24:317–325

    Article  CAS  PubMed  Google Scholar 

  13. Shoden A, Gabrio BW, Finch CA (1953) The relationship between ferritin and hemosiderin in rabbits and man. J Biol Chem 204:823–830

    CAS  PubMed  Google Scholar 

  14. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Wolff RK et al (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408

    Article  CAS  PubMed  Google Scholar 

  15. Pascoe A, Kerlin P, Steadman C, Clouston A, Jones D, Powell L, Jazwinska E, Lynch S, Strong R (1999) Spur cell anaemia and hepatic iron stores in patients with alcoholic liver disease undergoing orthotopic liver transplantation. Gut 45:301–305

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Sohda T, Takeyama Y, Irie M, Kamimura S, Shijo H (1999) Putative hemochromatosis gene mutations and alcoholic liver disease with iron overload in Japan. Alcohol Clin Exp Res 23:21S–23S

    Article  CAS  PubMed  Google Scholar 

  17. Dostalikova-Cimburova M, Kratka K, Stransky J, Putova I, Cieslarova B, Horak J (2012) Iron overload and HFE gene mutations in Czech patients with chronic liver diseases. Dis Markers 32:65–72

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Chapman RW, Morgan MY, Laulicht M, Hoffbrand AV, Sherlock S (1982) Hepatic iron stores and markers of iron overload in alcoholics and patients with idiopathic hemochromatosis. Dig Dis Sci 27:909–916

    Article  CAS  PubMed  Google Scholar 

  19. Bell H, Skinningsrud A, Raknerud N, Try K (1994) Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver diseases. J Intern Med 236:315–322

    Article  CAS  PubMed  Google Scholar 

  20. Suzuki Y, Saito H, Suzuki M, Hosoki Y, Sakurai S, Fujimoto Y, Kohgo Y (2002) Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease. Alcohol Clin Exp Res 26:26S–31S

    Article  CAS  PubMed  Google Scholar 

  21. Mueller S (2013) Non-invasive assessment of patients with alcoholic liver disease. Clin Liver Dis 2:68–71

    Article  Google Scholar 

  22. Mueller S (2013) The role of iron in alcoholic liver disease. Alcohol Alcohol 48:6

    Article  Google Scholar 

  23. Fenton HJ (1894) Oxidation of tartaric acid in presence of iron. J Chem Soc Trans 65:899–910

    Article  CAS  Google Scholar 

  24. Saran M, Michel C, Stettmaier K, Bors W (2000) Arguments against the significance of the Fenton reaction contributing to signal pathways under in vivo conditions. Free Radic Res 33:567–579

    Article  CAS  PubMed  Google Scholar 

  25. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G (1996) Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110:1107–1119

    Article  CAS  PubMed  Google Scholar 

  26. Ko C, Siddaiah N, Berger J, Gish R, Brandhagen D, Sterling RK, Cotler SJ, Fontana RJ, McCashland TM, Han SH, Gordon FD, Schilsky ML, Kowdley KV (2007) Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 27:1394–1401

    Article  PubMed  Google Scholar 

  27. Turlin B, Juguet F, Moirand R, Le Quilleuc D, Loreal O, Campion JP, Launois B, Ramee MP, Brissot P, Deugnier Y (1995) Increased liver iron stores in patients with hepatocellular carcinoma developed on a noncirrhotic liver. Hepatology 22:446–450

    CAS  PubMed  Google Scholar 

  28. Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, Malenka DJ, Ozaki CK, Lavori PW (2008) Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 100:996–1002

    Article  CAS  PubMed  Google Scholar 

  29. Hann HW, Stahlhut MW, Blumberg BS (1988) Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res 48:4168–4170

    CAS  PubMed  Google Scholar 

  30. Tsukamoto H, Horne W, Kamimura S, Niemela O, Parkkila S, Yla-Herttuala S, Brittenham GM (1995) Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 96:620–630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. D’Amico G, Garcia-Tsao G, Pagliaro L (2006) Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 44:217–231

    Article  PubMed  Google Scholar 

  32. Ganne-Carrie N, Christidis C, Chastang C, Ziol M, Chapel F, Imbert-Bismut F, Trinchet JC, Guettier C, Beaugrand M (2000) Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow up study. Gut 46:277–282

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Wang J, Pantopoulos K (2011) Regulation of cellular iron metabolism. Biochem J 434:365–381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Andrews NC (1999) Disorders of iron metabolism. N Engl J Med 341:1986–1995

    Article  CAS  PubMed  Google Scholar 

  35. Ganz T (2007) Molecular control of iron transport. J Am Soc Nephrol 18:394–400

    Article  CAS  PubMed  Google Scholar 

  36. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A 98:8780–8785

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Theil EC (2003) Ferritin: at the crossroads of iron and oxygen metabolism. J Nutr 133:1549S–1553S

    CAS  PubMed  Google Scholar 

  38. Nemeth E, Ganz T (2009) The role of hepcidin in iron metabolism. Acta Haematol 122:78–86

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Two to tango: regulation of mammalian iron metabolism. Cell 142:24–38

    Article  CAS  PubMed  Google Scholar 

  40. Sow FB, Florence WC, Satoskar AR, Schlesinger LS, Zwilling BS, Lafuse WP (2007) Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol 82:934–945

    Article  CAS  PubMed  Google Scholar 

  41. Weiss G, Goodnough LT (2005) Anemia of chronic disease. N Engl J Med 352:1011–1023

    Article  CAS  PubMed  Google Scholar 

  42. Millonig G, Ganzleben I, Peccerella T, Casanovas G, Brodziak-Jarosz L, Breitkopf-Heinlein K, Dick TP, Seitz HK, Muckenthaler MU, Mueller S (2012) Sustained submicromolar H2O2 levels induce hepcidin via signal transducer and activator of transcription 3 (STAT3). J Biol Chem 287:37472–37482

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Miura K, Taura K, Kodama Y, Schnabl B, Brenner DA (2008) Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 48:1420–1429

    Article  CAS  PubMed  Google Scholar 

  44. Ponka P, Beaumont C, Richardson DR (1998) Function and regulation of transferrin and ferritin. Semin Hematol 35:35–54

    CAS  PubMed  Google Scholar 

  45. Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, Koeffler HP (1999) Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 274:20826–20832

    Article  CAS  PubMed  Google Scholar 

  46. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP (2001) Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 98:2714–2719

    Article  CAS  PubMed  Google Scholar 

  47. Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Suryo Rahmanto Y, Sheftel AD, Ponka P (2010) Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci U S A 107:10775–10782

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Rouault TA (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2:406–414

    Article  CAS  PubMed  Google Scholar 

  49. Recalcati S, Minotti G, Cairo G (2010) Iron regulatory proteins: from molecular mechanisms to drug development. Antioxid Redox Signal 13:1593–1616

    Article  CAS  PubMed  Google Scholar 

  50. Wallander ML, Leibold EA, Eisenstein RS (2006) Molecular control of vertebrate iron homeostasis by iron regulatory proteins. Biochim Biophys Acta 1763:668–689

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Lok CN, Ponka P (2000) Identification of an erythroid active element in the transferrin receptor gene. J Biol Chem 275:24185–24190

    Article  CAS  PubMed  Google Scholar 

  52. Torti FM, Torti SV (2002) Regulation of ferritin genes and protein. Blood 99:3505–3516

    Article  CAS  PubMed  Google Scholar 

  53. Ponka P, Lok CN (1999) The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 31:1111–1137

    Article  CAS  PubMed  Google Scholar 

  54. Piccinelli P, Samuelsson T (2007) Evolution of the iron-responsive element. RNA 13:952–966

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Deck KM, Vasanthakumar A, Anderson SA, Goforth JB, Kennedy MC, Antholine WE, Eisenstein RS (2009) Evidence that phosphorylation of iron regulatory protein 1 at Serine 138 destabilizes the [4Fe-4S] cluster in cytosolic aconitase by enhancing 4Fe-3Fe cycling. J Biol Chem 284:12701–12709

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Sanchez M, Galy B, Muckenthaler M, Hentze MW (2007) Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat Struct Mol Biol 14:420–426

    Article  CAS  PubMed  Google Scholar 

  57. Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A, Sun D, Bhaskaran N, Persson A, Uhlen M, Sangfelt O, Spruck C, Leibold EA, Wohlschlegel JA (2009) Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326:718–721

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Salahudeen AA, Thompson JW, Ruiz JC, Ma HW, Kinch LN, Li Q, Grishin NV, Bruick RK (2009) An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326:722–726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Fillebeen C, Pantopoulos K (2002) Redox control of iron regulatory proteins. Redox Rep 7:15–22

    Article  CAS  PubMed  Google Scholar 

  60. Mueller S (2005) Iron regulatory protein 1 as a sensor of reactive oxygen species. Biofactors 24:171–181

    Article  CAS  PubMed  Google Scholar 

  61. Mutze S, Hebling U, Stremmel W, Wang J, Arnhold J, Pantopoulos K, Mueller S (2003) Myeloperoxidase-derived hypochlorous acid antagonizes the oxidative stress-mediated activation of iron regulatory protein 1. J Biol Chem 278:40542–40549

    Article  PubMed  Google Scholar 

  62. Watts RN, Hawkins C, Ponka P, Richardson DR (2006) Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1. Proc Natl Acad Sci U S A 103:7670–7675

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Hillman RS (1975) Alcohol and hematopoiesis. In: Seixas FA, Williams K, Seggleston S (eds) Medical consequences of alcoholism. New York Academy of Sciences, New York

    Google Scholar 

  64. Hines JD (1975) Hematologic abnormalities involving vitamin B6 and folate metabolism in alcoholic subjects. In: Seixas FA, Williams K, Seggleston S (eds) Medical consequences of alcoholism. New York Academy of Sciences, New York

    Google Scholar 

  65. Lumeng L, Li TK (1974) Vitamin B6 metabolism in chronic alcohol abuse. J Clin Invest 53:698

    Article  Google Scholar 

  66. Herbert V, Tisman G (1975) Hematologic effects of alcohol. In: Seixas FA, Williams K, Seggleston S (eds) Medical consequences of alcoholism. New York Academy of Sciences, New York

    Google Scholar 

  67. Scharf R, Aul C (1988) Alcohol-induced disorders of the hematopoietic system. Z Gastroenterol 26(Suppl 3):75–83

    CAS  PubMed  Google Scholar 

  68. Eichner ER (1973) The hematologic disorders of alcoholism. Am J Med 54:621–630

    Article  CAS  PubMed  Google Scholar 

  69. Lindenbaum J (1987) Hematologic complications of alcohol abuse. Semin Liver Dis 7:169–181

    Article  CAS  PubMed  Google Scholar 

  70. Niemela O, Parkkila S (2004) Alcoholic macrocytosis—is there a role for acetaldehyde and adducts? Addict Biol 9:3–10

    Article  PubMed  Google Scholar 

  71. Pitcher CS, Williams R (1963) Reduced red cell survival in jaundice and its relation to abnormal glutathione metabolism. Clin Sci 24:239–252

    CAS  PubMed  Google Scholar 

  72. Krasnow SE, Walsh JR, Zimmerman HJ, Heller P (1957) Megaloblastic anemia in alcoholic cirrhosis. AMA Arch Intern Med 100:870–880

    Article  CAS  PubMed  Google Scholar 

  73. Maturu P, Reddy VD, Padmavathi P, Varadacharyulu N (2012) Ethanol induced adaptive changes in blood for the pathological and toxicological effects of chronic ethanol consumption in humans. Exp Toxicol Pathol 64:697–703

    Article  CAS  PubMed  Google Scholar 

  74. McClain CJ, Barve SS, Barve A, Marsano L (2011) Alcoholic liver disease and malnutrition. Alcohol Clin Exp Res 35:815–820

    Article  PubMed Central  PubMed  Google Scholar 

  75. Mezey E (1975) Intestinal function in chronic alcoholism. In: Seixas FA, Williams K, Seggleston S (eds) Medical consequences of alcoholism. New York Academy of Sciences, New York

    Google Scholar 

  76. Madden AM, Bradbury W, Morgan MY (1997) Taste perception in cirrhosis: its relationship to circulating micronutrients and food preferences. Hepatology 26:40–48

    Article  CAS  PubMed  Google Scholar 

  77. Mezey E (1982) Liver disease and protein needs. Annu Rev Nutr 2:21–50

    Article  CAS  PubMed  Google Scholar 

  78. Hanje AJ, Fortune B, Song M, Hill D, McClain C (2006) The use of selected nutrition supplements and complementary and alternative medicine in liver disease. Nutr Clin Pract 21:255–272

    Article  PubMed Central  PubMed  Google Scholar 

  79. Stickel F, Hoehn B, Schuppan D, Seitz HK (2003) Review article: Nutritional therapy in alcoholic liver disease. Aliment Pharmacol Ther 18:357–373

    Article  CAS  PubMed  Google Scholar 

  80. Ohtake T, Saito H, Hosoki Y, Inoue M, Miyoshi S, Suzuki Y, Fujimoto Y, Kohgo Y (2007) Hepcidin is down-regulated in alcohol loading. Alcohol Clin Exp Res 31:S2–S8

    Article  PubMed  Google Scholar 

  81. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, Fein E, Andriopoulos B, Pantopoulos K, Gollan J (2006) Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem 281:22974–22982

    Article  CAS  PubMed  Google Scholar 

  82. Harrison-Findik DD, Klein E, Crist C, Evans J, Timchenko N, Gollan J (2007) Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 46:1979–1985

    Article  CAS  PubMed  Google Scholar 

  83. Harrison-Findik DD, Klein E, Evans J, Gollan J (2009) Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-alpha signaling. Am J Physiol Gastrointest Liver Physiol 296:G112–G118

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Shindo M, Torimoto Y, Saito H, Motomura W, Ikuta K, Sato K, Fujimoto Y, Kohgo Y (2006) Functional role of DMT1 in transferrin-independent iron uptake by human hepatocyte and hepatocellular carcinoma cell, HLF. Hepatol Res 35:152–162

    CAS  PubMed  Google Scholar 

  85. Suzuki M, Fujimoto Y, Suzuki Y, Hosoki Y, Saito H, Nakayama K, Ohtake T, Kohgo Y (2004) Induction of transferrin receptor by ethanol in rat primary hepatocyte culture. Alcohol Clin Exp Res 28:98S–105S

    Article  CAS  PubMed  Google Scholar 

  86. Andriopoulos B, Hegedusch S, Mangin J, Hd R, Hebling U, Wang J, Pantopoulos K, Mueller S (2007) Sustained hydrogen peroxide induces iron uptake by transferrin receptor-1 independent of the iron regulatory protein/iron-responsive element network. J Biol Chem 282:20301–20308

    Article  CAS  PubMed  Google Scholar 

  87. Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidaka I, Okita K, Sakaida I (2008) Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134:226–238

    Article  CAS  PubMed  Google Scholar 

  88. Ren Y, Deng F, Zhu H, Wan W, Ye J, Luo B (2011) Effect of epigallocatechin-3-gallate on iron overload in mice with alcoholic liver disease. Mol Biol Rep 38:879–886

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by the Dietmar-Hopp-Stiftung and the Manfred-Lautenschläger-Stiftung.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121, Heidelberg, Germany

    Sebastian Mueller & Vanessa Rausch

Authors
  1. Sebastian Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vanessa Rausch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sebastian Mueller .

Editor information

Editors and Affiliations

  1. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA

    Vasilis Vasiliou

  2. Distilled Spirits Council of the United States, Washington, District of Columbia, USA

    Samir Zakhari

  3. Centre of Alcohol Research, University of Heidelberg, Germany and Salem Medical Centre, Heidelberg, Germany

    Helmut K. Seitz

  4. Department of Pathology, Anatomy, & Cell, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Jan B. Hoek

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this paper

Cite this paper

Mueller, S., Rausch, V. (2015). The Role of Iron in Alcohol-Mediated Hepatocarcinogenesis. In: Vasiliou, V., Zakhari, S., Seitz, H., Hoek, J. (eds) Biological Basis of Alcohol-Induced Cancer. Advances in Experimental Medicine and Biology, vol 815. Springer, Cham. https://doi.org/10.1007/978-3-319-09614-8_6

Download citation

Publish with us

Policies and ethics

Search

Navigation