Lipid Peroxidation and Associated Hepatic Organelle Dysfunction in Iron Overload

  • B. R. Bacon
  • R. S. Britton
  • R. O’Neill

Abstract

It has recently been recognized that genetic hemochromatosis (GH) is one of the most common inherited disorders. Approximately 0.1%–0.8% of whites of northern European ancestry are affected and the frequency of heterozygotes is thought to be about 5%–16% of the population [7, 12, 17, 20, 24, 34, 39, 43, 44, 53, 54]. In GH, there is an inappropriate increase in intestinal absorption of iron leading to progressive deposition of excess iron in parenchymal cells of the liver and several other organs [26, 28, 41, 47, 56]. The liver is the major recipient of the excess absorbed iron and after several years of high tissue iron concentrations, fibrosis and eventually cirrhosis develop [8, 38, 42, 56]. In addition, excess iron deposition in the liver is found in a variety of other disorders leading to secondary iron overload (e.g., thalassemia, chronic liver disease, porphyria cutanea tarda, sideroblastic anemia, African iron overload) [8, 26, 38, 41, 56].

Keywords

Glutathione Respiration Selenium Carbonyl Alkane 

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References

  1. 1.
    Bacon BR, Brittenham GM, Tavill AS, McLaren CE, Park CH, Recknagel RO (1983a) Hepatic lipid peroxidation in vivo in rats with chronic dietary iron overload is dependent on hepatic iron concentration. Trans Assoc Am Physicians 96: 146–154PubMedGoogle Scholar
  2. 2.
    Bacon BR, Tavill AS, Brittenham GM, Park CH, Recknagel RO (1983b) Hepatic lipid peroxidation in vivo in rats with chronic iron overload. J Clin Invest 71: 429–439PubMedCrossRefGoogle Scholar
  3. 3.
    Bacon BR, Park CH, Brittenham GM, O’Neill R, Tavill AS (1985) Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload. Hepatology 5: 789–797PubMedCrossRefGoogle Scholar
  4. 4.
    Bacon BR, Healey JF, Brittenham GM, Park CH, Nunnari J, Tavill AS, Bonkovsky HL (1986) Hepatic microsomal function in rats with chronic dietary iron overload. Gastroenterology 90: 1844–1853PubMedGoogle Scholar
  5. 5.
    Bacon BR, Britton RS, O’Neill R (1989) Effects of vitamin E deficiency on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload. Hepatology 9: 398–404Google Scholar
  6. 6.
    Barry M, Flynn DM, Letsky EA, Risdon RA (1974) Long-term chelation therapy in thalassemia major: effect on liver iron concentration, liver histology and clinical progress. Br Med J 2: 16–20PubMedCrossRefGoogle Scholar
  7. 7.
    Bassett M, Doran TJ, Halliday JW, Bashir HV, Powell LW (1982) Idiopathic hae- mochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families. Hum Genet 60: 352–356PubMedCrossRefGoogle Scholar
  8. 8.
    Bassett ML, Halliday JW, Powell LW (1984) Genetic hemochromatosis. Semin Liver Dis 4: 217–227PubMedCrossRefGoogle Scholar
  9. 9.
    Bassett ML, Halliday JW, Powell LW (1986) Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 6: 24–29PubMedCrossRefGoogle Scholar
  10. 10.
    Bomford A, Williams R (1976) Long-term results of venesection therapy in idiopathic haemochromatosis. Q J Med 45: 611–623PubMedGoogle Scholar
  11. 11.
    Bonkowsky HL, Healey JF, Sinclair PR, Sinclair JF, Pomeroy, JS (1981) Iron and the liver: acute and long-term effects of iron loading on hepatic haem metabolism. Biochem J 196: 57–64PubMedGoogle Scholar
  12. 12.
    Borwein ST, Ghent CN, Flanagan PR, Chamberlain MJ, Valberg LS (1983) Genetic and phenotypic expression of hemochromatosis in Canadians. Clin Invest Med 6: 171–179PubMedGoogle Scholar
  13. 13.
    Britton RS, Bacon BR, Recknagel RO (1987) Lipid peroxidation and associated hepatic organelle dysfunction in iron overload. Chem Phys Lipids 45: 207–239PubMedCrossRefGoogle Scholar
  14. 14.
    Britton RS, Ferrali M, Magiera CJ, Recknagel RO, Bacon BR (1990a) Increased prooxidant action of hepatic cytosolic low-molecular-weight iron in experimental iron overload. Hepatology 11: 1038–1043PubMedCrossRefGoogle Scholar
  15. 15.
    Britton RS, O’Neill R, Bacon BR (1990b) Hepatic mitochondrial malondialdehyde metabolism in rats with chronic iron overload. Hepatology 11: 93–97PubMedCrossRefGoogle Scholar
  16. 16.
    Britton RS, O’Neill R, Bacon BR (1991) Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes. Gastro-enterology 101: 806–811Google Scholar
  17. 17.
    Cartwright GE, Edwards CQ, Kravitz K, Skolnick M, Amos DB, Johnson A, Buskjaer L (1979) Hereditary hemochromatosis. Phenotypic expression of the disease. N Engl J Med 301: 175–179Google Scholar
  18. 18.
    Chojkier M, Houglum K, Solis-Herruzo J, Brenner DA (1989) Stimulation of collagen gene expression by ascorbic acid in cultured human fibroblasts. A role for lipid peroxidation? J Biol Chem 264: 16957–16962PubMedGoogle Scholar
  19. 19.
    Cohen A, Witzleben C, Schwartz E (1984) Treatment of iron overload. Semin Liver Dis 4: 228–238PubMedCrossRefGoogle Scholar
  20. 20.
    Dadone MM, Kushner JP, Edwards CQ, Bishop DT, Skolnik MH (1982) Hereditary hemochromatosis: analysis of laboratory expression of the disease by genotype in 18 pedigrees. Am J Clin Pathol 78: 196–207PubMedGoogle Scholar
  21. 21.
    de Matteis F, Sparks RG (1973) Iron-dependent loss of liver cytochrome P-450 haem in vivo and in vitro. FEBS Lett 29: 141–144PubMedCrossRefGoogle Scholar
  22. 22.
    Dillard CJ, Tappel AL (1979) Volatile hydrocarbon and carbonyl products of lipid peroxidation: a comparison of pentane, ethane, hexanal and acetone as in vivo indices. Lipids 14: 989–995PubMedCrossRefGoogle Scholar
  23. 23.
    Dillard CJ, Downey JE, Tappel AL (1984) Effects of antioxidants on lipid peroxidation in iron-loaded rats. Lipids 19: 127–133PubMedCrossRefGoogle Scholar
  24. 24.
    Edwards CQ, Griffin LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP (1988) Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318: 1355–1362PubMedCrossRefGoogle Scholar
  25. 25.
    Golberg L, Martin LE, Batchelor A (1962) Biochemical changes in the tissues of animals injected with iron. 3. Lipid peroxidation. Biochem J 83: 291–298Google Scholar
  26. 26.
    Gordeuk VR, Bacon BR, Brittenham GM (1987) Iron overload: causes and consequences. Annu Rev Nutr 7: 485–508PubMedCrossRefGoogle Scholar
  27. 27.
    Groskreutz JL, Bronk SF, Gores GJ (1990) Oxidative injury of hepatocytes: mechanisms of lethal injury and protection by ruthenium red. Gastroenterology 98: A590Google Scholar
  28. 28.
    Holland HK, Spivak JL (1989) Hemochromatosis. Med Clin North Am 73: 831–845PubMedGoogle Scholar
  29. 29.
    Hruszkewycz AM (1988) Evidence of mitochondrial DNA damage by lipid peroxidation. Biochem Biophys Res Commun 153: 191–197PubMedCrossRefGoogle Scholar
  30. 30.
    Hultcrantz R, Ahlberg J, Glaumann H (1984a) Isolation of two lysosomal populations from iron-overloaded rat liver with different iron concentration and proteolytic activity. Virchows Arch [Cell Pathol] 47: 55–65CrossRefGoogle Scholar
  31. 31.
    Hultcrantz R, Ericsson JLE, Hirth T (1984b) Levels of malondialdehyde production in rat liver following loading and unloading of iron. Virchows Arch [Cell Pathol] 45: 139–146CrossRefGoogle Scholar
  32. 32.
    Isaacson C, Seftel HL, Keeley KJ, Bothwell TH (1961) Siderosis in the Bantu. The relationship between iron overload and cirrhosis. J Lab Clin Med 58: 845–853Google Scholar
  33. 33.
    LeSage GD, Kost LJ, Barham SS, LaRusso NF (1986) Biliary excretion of iron from hepatocyte lysosomes in the rat: a major excretory pathway in experimental iron overload. J Clin Invest 77: 90–97PubMedCrossRefGoogle Scholar
  34. 34.
    Lindmark B, Eriksson S (1985) Regional differences in the idiopathic hemochromatosis gene frequency in Sweden. Acta Med Scand 218: 299–304PubMedCrossRefGoogle Scholar
  35. 35.
    Louw M, Neethling AC, Percy VA, Carstens M, Shanley BC (1977) Effects of hexachlorobenzene feeding and iron overload on enzymes of haem biosynthesis and cytochrome P-450 in rat liver. Clin Sei 53: 111–115Google Scholar
  36. 36.
    Masini A, Ceccarelli-Stanzani D, Trenti T, Ventura E (1984a) Transmembrane potential of liver mitochondria from hexachlorobenzene- and iron-treated rats. Biochim Biophys Acta 802: 253–258PubMedCrossRefGoogle Scholar
  37. 37.
    Masini A, Trenti T, Ventura E, Ceccarelli-Stanzani D, Muscatello U (1984b) Functional efficiency of mitochondrial membrane of rats with hepatic chronic iron overload. Biochem Biophys Res Commun 124: 462–469PubMedCrossRefGoogle Scholar
  38. 38.
    McLaren GD, Muir WA, Kellermeyer RW (1983) Iron overload disorders: natural history, pathogenesis, diagnosis and therapy. CRC Crit Rev Clin Lab Sei 19: 205–266CrossRefGoogle Scholar
  39. 39.
    Meyer TE, Ballot D, Bothwell TH, Green A, Derman DP, Baynes RD, Jenkins T, Jooste PL, du Toit ED, Jacobs P (1987) The HLA linked iron loading gene in an Afrikaner population. J Med Genet 24: 348–356PubMedCrossRefGoogle Scholar
  40. 40.
    Myers BM, Prendergast FG, LaRusso NF (1988) Experimental iron overload increases the pH of hepatic lysosomes. Hepatology 8: 1240Google Scholar
  41. 41.
    Nichols GM, Bacon BR (1989) Hereditary hemochromatosis: pathogenesis and clinical features of a common disease. Am J Gastroenterol 84: 851–862PubMedGoogle Scholar
  42. 42.
    Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G (1985) Survival and causes of death in cirrhotic and noncirrhotic patients with primary hemochromatosis. N Engl J Med 313: 1256–1262PubMedCrossRefGoogle Scholar
  43. 43.
    Olsson KS, Ritter B, Rosen U, Heedman PA, Staugard F (1983) Prevalence of iron overload in central Sweden. Acta Med Scand 213: 145–150PubMedCrossRefGoogle Scholar
  44. 44.
    Olsson KS, Eriksson K, Ritter B, Heedman PA (1984) Screening for iron overload using transferrin saturation. Acta Med Scand 215: 105–112PubMedCrossRefGoogle Scholar
  45. 45.
    Park CH, Bacon BR, Brittenham GM, Tavill AS (1987) Pathology of dietary carbonyl iron overload in rats. Lab Invest 57: 555–563PubMedGoogle Scholar
  46. 46.
    Peters TJ, O’Connell MJ, Ward RJ (1985) Role of free-radical mediated lipid peroxidation in the pathogenesis of hepatic damage by lysosomal disruption. In: Poli G, Cheeseman KH, Dianzani MU, Slater TF (eds) Free radicals in liver injury. IRL, Oxford, pp 107–115Google Scholar
  47. 47.
    Powell LW, Halliday JW (1980) Idiopathic haemochromatosis. In: Jacobs A, Worwood M (eds) Iron in biochemistry and medicine, vol 2. Academic, New York, pp 461–498Google Scholar
  48. 48.
    Risdon RA, Barry M, Flynn DM (1975) Transfusional iron overload: the relationship between tissue iron concentration and hepatic fibrosis in thalassemia. J Pathol 116: 83–95PubMedCrossRefGoogle Scholar
  49. 49.
    Seiden C, Seymour CA, Peters TJ (1980) Activities of some free-radical scavenging enzymes and glutathione concentrations in human and rat liver and their relationship to the pathogenesis of tissue damage in iron overload. Clin Sei 58: 211–219Google Scholar
  50. 50.
    Seymour CA, Peters TJ (1978) Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes. Br J Haematol 40: 239–253PubMedCrossRefGoogle Scholar
  51. 51.
    Sharma BK, Bacon BR, Britton RS, Park CH, Magiern CJ, O’Neill R, Dalton N, Smanik P, Speroff T (1990) Prevention of hepatocyte injury and lipid peroxidation by iron chelators and a-tocopherol in isolated iron-loaded rat hepatocytes. Hepatology 12: 31–39PubMedCrossRefGoogle Scholar
  52. 52.
    Shires TK (1982) Iron-induced DNA damage and synthesis in isolated rat liver nuclei. Biochem J 205: 321–329PubMedGoogle Scholar
  53. 53.
    Simon M, Alexandre, J-L, Fauchet R, Genetet B, Bourel M (1980) The genetics of hemochromatosis. Prog Med Genet 4: 135–168PubMedGoogle Scholar
  54. 54.
    Tanner AR, Desai S, Lu W, Wright R (1985) Screening for haemochromatosis in the UK: preliminary results. Gut 26: 1139–1140AGoogle Scholar
  55. 55.
    Tappel AL (1980) Vitamin E and selenium protection from in vivo lipid peroxidation. Ann NY Acad Sci 355: 18–31Google Scholar
  56. 56.
    Tavill AS, Bacon BR (1990) Hemochromatosis: iron metabolism and the iron overload syndromes. In: Zakim D, Boyer TD (eds) Hepatology: a textbook of liver disease. Saunders, Philadelphia, pp 1273–1299Google Scholar
  57. 57.
    Thomas CE, Reed DJ (1988) Effect of extracellular Ca++ omission on isolated hepatocytes. II. Loss of mitochondrial membrane potential and protection by inhibitors of uniport Ca++ transduction. J Pharmacol Exp Ther 245: 501–507PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • B. R. Bacon
  • R. S. Britton
  • R. O’Neill

There are no affiliations available

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