Biological Trace Element Research

, Volume 51, Issue 2, pp 177–197 | Cite as

Iron accumulation in tissues of magnesium-deficient rats with dietary iron overload

Experimental hemochromatosis model
  • Mieko Kimura
  • Katsuhiko Yokoi


The mineral imbalances in magnesium-deficient rats with dietary iron overload were studied. Forty-four male Wister rats were divided into six groups and fed six diets, two by three, fully crossed: magnesium adequate or deficient, and iron deficient, adequate, or excess. The concentrations of iron, magnesium, calcium, and phosphorus in tissues of the rats were measured. The results were as follows: (1) The excess iron intake reinforced the iron accumulation in liver and spleen of magnesium deficient rats; (2) The saturation of iron binding capacity was enormously elevated in the magnesium deficient rats fed excess iron; and (3) Dietary iron deprivation diminished the degree of calcium deposition in kidney of magnesium deficient rats. These results suggest that magnesium-deprived-rats have abnormal iron metabolism losing homeostatic regulation of plasma iron, and magnesium deficient rats with dietary iron overload may be used as an experimental hemochromatosis model.

Index Entries

Magnesium deficiency iron accumulation iron overload rats mineral imbalance phosphorus calcium 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J. Kobayashi, Geographical relation between the chemical nature of river water and death-rate from apoplexy,Ber. Ohara Inst. Landw. Biol. 11, 12–21 (1957).Google Scholar
  2. 2.
    H. A. Schroeder, Degenerative cardiovascular disease in the orient. Hypertension,J. Chron. Dis. 8, 125–129 (1966).Google Scholar
  3. 3.
    J. R. Marier and C. L. Neri, Quantifying the role of magnesium in the interrelationship between mortality/morbidity and water hardness.Magnesium 4, 53–59, (1985).PubMedGoogle Scholar
  4. 4.
    M. D. Crawford and M. J. Gardner, Prevalence and pathological changes in ischaemic heart disease in hard water and a soft-water area,Lancet i, 229–232 (1967).CrossRefGoogle Scholar
  5. 5.
    S. de Fulvio and L. Olori, Definitions and classification of naturally soft and naturally hard water, inAmavis, Hardness of Drinking Water and Public Health, eds., Pergamon New York, pp. 95–122 (1975).Google Scholar
  6. 6.
    J. Durlach, M. Bara, and A. Guiet-Bara, Magnesium level in drinking water and cardiovascular risk factor. A hypothesis,Magnesium 4, 5–15 (1985).PubMedGoogle Scholar
  7. 7.
    M. S. Seelig and H. A. Heggtveit, Magnesium interrelationships in ischemic heart disease,Am. J. Clin. Nutr. 27, 59–79 (1974).PubMedGoogle Scholar
  8. 8.
    E. B. Flink, Magnesium deficiency. Etiology and clinical spectrum,Acta Med. Scand. 125–137 (1981).Google Scholar
  9. 9.
    G. E. Burch and T. D. Giles, The importance of magnesium deficiency in cardiovascular disease,Am. Heart J. 94, 649–657 (1977).PubMedCrossRefGoogle Scholar
  10. 10.
    L. T. Iseri, J. Freed, and A. R. Bures, Magnesium deficiency and cardiac disorders,Am. J. Med. 58, 837–846 (1975).PubMedCrossRefGoogle Scholar
  11. 11.
    B. Chipperfield and J. R. Chipperfield, Magnesium and the heart,Am. Heart J. 93, 679–682 (1977).PubMedCrossRefGoogle Scholar
  12. 12.
    Y. Itokawa, Recent aspects of magnesium and cardiovascular diseases, inNew Horizons in Preventing Cardiovascular Diseases, Y. Yamori and T. Strasser, eds., Elsevier Science Publishers, New York, pp. 27–34 (1989).Google Scholar
  13. 13.
    B. Chipperfield and J. R. Chipperfield, Differences in metal content of the heart muscle in death from ischemic heart disease,Am. Heart J. 95, 732–737 (1978).PubMedCrossRefGoogle Scholar
  14. 14.
    M. Kimura, N. Sato, and Y. Itokawa, Thiamin status of inhabitants on North-East Thailand,Trace Nutrients Res. (Kyoto),4, 163–170 (1988).Google Scholar
  15. 15.
    T. Takeda, M. Kimura, K. Yokoi, and Y. Itokawa, Blood mineral status of patients in geriatric hospital—relationship between magnesium and other, mineral.JJSMgR 9, 211–219 (1990) (Japanese).Google Scholar
  16. 16.
    M. Kimura and Y. Itokawa, Effects of calcium and magnesium deficiency on thiamine distribution in rat brain and liver,J. Neurochem. 28, 389–393 (1977).PubMedCrossRefGoogle Scholar
  17. 17.
    Y. Itokawa, S. Sasagawa, and M. Fujiwara, Effect of thiamine on lipid metabolism in magnesium deficient rats.J. Nutr. Sci. Vitaminol. 19, 15–21 (1973).PubMedGoogle Scholar
  18. 18.
    F. H. Nielsen, T. R. Shuler, T. J. Zimmerman, and E. O. Uthus, Magnesium and methionine deprivation affect the response of rats to boron deprivation,Biol. Trace Elem. Res. 17, 91–107 (1988).PubMedGoogle Scholar
  19. 19.
    M. Kimura and Y. Itokawa, Inefficient utilization of iron and minerals in magnesium deficient rats, inMagnesium in Health and Diease, Y. Itokawa and J. Durlach, eds., John Libbey, London, pp. 95–102 (1989).Google Scholar
  20. 20.
    R. Whang and L. G. Welt, Observation in experimental magnesium depletion.,J. Lab. Clin. Med. 42, 305–313 (1963).Google Scholar
  21. 21.
    Z. Zhu, M. Kimura, and Y. Itokawa, Selenium concentration and glutathione peroxidase activity in selenium and magnesium deficient rats,Biol. Trace Elemen. Res. 37, 209–217 (1993).Google Scholar
  22. 22.
    Y. Itokawa and M. Kimura, Effect of magnesium deficiency on thiamin metabolism,Mag. Bull. 4, 5–8 (1982).Google Scholar
  23. 23.
    M. Kimura, A. Matsuda, M. Ujihara, H. Kondo, T. Notani, and Y. Itokawa, Manganese deficiency induced by magnesium deficiency in rats.Magnesium (Kyoto) 9, 93–99 (1990) (Japanese).Google Scholar
  24. 24.
    M. Kimura, M. Ujihara, and Y. Itokawa, Changes of manganese concentration in various tissues and pyruvate carboxylase activity in liver of magnesium deficient rats,Trace Nutrients Res. (Kyoto) 7, 131–138 (1990) (Japanese).Google Scholar
  25. 25.
    M. Kimura, K. Yokoi, M. Hayase, and Y. Itokawa, Effects of iron intake on serum biochemical parameters in mangnesium deficient rats,JJSMgR 11, 19–29 (1992) (Japanese).Google Scholar
  26. 26.
    S. M. Ahmed, M. Kimura, and Y. Itokawa, Iron and zinc status of protein-energy malnourished rats.Trace Nutrients Res. (Kyoto) 4 121–126 (1988).Google Scholar
  27. 27.
    J. Y. Yu and Y. Cho, Tissue iron content in riboflavin and pyridoxine deficient rats,J. Nutr. Biochem. 1, 310–314 (1990).PubMedCrossRefGoogle Scholar
  28. 28.
    K. Yokoi, M. Kimura, and Y. Itokawa, Mineral status in copper-deficient rats,Trace Nutrients Res. (Kyoto),7, 125–130 (1990) (Japanese).Google Scholar
  29. 29.
    Z. Zhu, M. Kimura, and Y. Itokawa, Mineral status in selenium-deficient rats compered to selenium-sufficient rats fed vitamin-free casein-based or Torula yeast-based diet,Biol. Trace Elem. Res. 37, 219–231 (1993).PubMedGoogle Scholar
  30. 30.
    M. S. Mameesh and B. C. Johnson, The effect of penicillin on the intestinal synthesis of thiamine in the rat,J. Nutr. 65, 161–167 (1958).PubMedGoogle Scholar
  31. 31.
    D. F. Bainton and C. A. Finch, Diagnosis of iron deficiency anaemia,Am. J. Med. 37, 62–70 (1964).PubMedCrossRefGoogle Scholar
  32. 32.
    G. J. Schmidt and W. Slavin, Inductively coupled plasma emission spectrometry with internal standardization and subtraction of plasma background fluctuations,Anal. Chem. 54, 2491–2495 (1982).CrossRefGoogle Scholar
  33. 33.
    K. Yokoi, M. Kimura, and Y. Itokawa, Determination of nonheme iron using inductuvely coupled plasma-atomic emission spectrometry,Biol. Trace Elem. Res. 31, 265–279 (1991).PubMedGoogle Scholar
  34. 34.
    B. Hallgren, Haemoglobin formation and storage iron in protein deficiency,Acta Soc. Med. 59, 79–208 (1954).Google Scholar
  35. 35.
    J. W. Drysdale and W. N. M. Ramsay, The separation of ferritin and haemosiderin for studies in the metabolism of iron,Biochem. J. 95, 282–288 (1965).PubMedGoogle Scholar
  36. 36.
    Y. Tanaka, T. Tamuri, and K. Wakimoto, eds.Handbook for Statistical Analysis with the Personal Computer, vol. 5,Multivatiate Analysis of Variance and Linear Model, Kyoritsu Syuppan, Tokyo, Japan, 1990 (Japanese).Google Scholar
  37. 37.
    H. D. Kruse, E. R. Orent, and E. V. McCollum, Studies on magnesium deficiency in animals. I. symptomatology resulting from magnesium deprivation,J. Biol. Chem. 96, 519–539 (1932).Google Scholar
  38. 38.
    S. Q. Cohlan, V. Jansen, J. Dancis, and S. Piomelli, Microcytic anemia with erythroblastosis in offspring of magnesium-deprived rats,Blood 36, 500–506 (1970).PubMedGoogle Scholar
  39. 39.
    S. Tao, B. E. Fry, and F. M. R. Spiny, Magnesium stores and anemia in young Japanese quail,J. Nutr. 113, 1195–1203 (1983).PubMedGoogle Scholar
  40. 40.
    H. N. Munro and M. C. Linder, Ferritin: structure, biosynthesis, and role in iron metabolism,Physiol. Rev. 58, 317–396 (1978).PubMedGoogle Scholar
  41. 41.
    H. G. du Defaix, R. Puente, B. Vidal, E. Perez, and H. Vidal, Liver storage iron in normal population of Cuba,Am. J. Clin. Nutr. 33, 133–136 (1980).Google Scholar
  42. 42.
    B. W. Gabrio, A. Shoden, and C. A. Finch, A quantitative fractionation of tissue ferritin and hemosiderin,J. Biol. Chem. 204, 815–821 (1953).PubMedGoogle Scholar
  43. 43.
    G. S. McKnight, D. C. Lee, and R. D. Palmiter, Transferrin gene expression: regulation of mRNA transcription in chick liver by steroid hormones and iron deficiency,J. Biol. Chem. 255, 148–153 (1980).PubMedGoogle Scholar
  44. 44.
    R. L. Idzerda, H. Huebers, C. A. Finch, and G. S. McKnight, Rat transferrin gene expression: tissue specific regulation by iron deficiency,Proc. Natl. Acad. Sci. USA 83, 3723–3727 (1986).PubMedCrossRefGoogle Scholar
  45. 45.
    M. A. Siimes, C. Refino, and P. R. Dallman, Manifestation of iron deficiency at various levels of dietary iron intake,Am. J. Clin. Nutr. 33, 570–574 (1980).PubMedGoogle Scholar
  46. 46.
    S. C. Madden, F. W. Anderson, J. C. Donovan, and G. H. Whipple, Plasma protein production influenced by amino acid mixtures and lack of essential amino acids,J. Exper. Med. 82, 77–92 (1945).CrossRefGoogle Scholar
  47. 47.
    L. L. Miller, C. G. Bly, M. L. Watson, and W. F. Bale, The dominant role of the liver in plasma protein synthesis,J. Exper. Med. 94, 431–453 (1951).CrossRefGoogle Scholar
  48. 48.
    E. H. Morgan, Synthesis and secretion of transferrin, inPlasma Protein Secretion by the Liver, H. Glaumann, T. Peters and C. Redman, eds., Academic, London, pp. 331–355 (1983).Google Scholar
  49. 49.
    T. Diamond, D. Stiel, and S. Posen, Osteoprosis in hemochromatosis: iron excess, gonadal deficiency, or other factors?,Ann. Int. Med. 110, 430–436 (1989).PubMedGoogle Scholar
  50. 50.
    R. A. MacDonald, B. J. P. Becker, and G. S. Pechet, Iron and liver disease in South Africa,Arch. Int. Med. 111, 315–322 (1963).Google Scholar
  51. 51.
    H. C. Seftel, C. Malkin, A. Schmaman, C. Abrahams, S. R. Lynch, R. W. Charlton, and T. H. Bothwell, Osteoporosis, scurvy and siderosis in Johannesburg Bantu,Brit. Med. J. 1, 642–646 (1966).PubMedGoogle Scholar
  52. 52.
    S. R. Lynch, I. Berelowitz, H. C. Seftel, G. B. Miller, P. Krawitz, R. W. Charlton, and T. H. Bothwell Osteoporosis in Johannesburg Bantu males. Its relationship to siderosis and ascorbic acid deficiency,Am. J. Clin. Nutr. 20, 799–807 (1967).PubMedGoogle Scholar
  53. 53.
    A. P. MacPhail, M. O. Simon, J. D. Torrance, R. W. Charlton, T. H. Bothwell, and C. Isaacson, Changing patterns of dietary iron overload in black South Africans,Am. J. Clin. Nutr. 32, 1272–1278 (1979).PubMedGoogle Scholar
  54. 54.
    V. Gordeuk, J. Mukibi, S. J. Hasstedt, W. Samowitz, C. Q. Edwards, G. West, S. Ndambire, J. Emmanual, N. Nkanza, Z. Chapanduka, M. Randall, P. Boone, P. Romano, R. W. Martell, T. Yamashita, P. Effler, and G. Brittenham, Iron overload in Africa. Interaction between a gene and dietary iron content,N. Engl. J. Med. 326, 95–100 (1992).PubMedCrossRefGoogle Scholar
  55. 55.
    A. Jacobs, Iron overload—clinical and pathologic aspects,Semin. Hematol. 14, 89–113 (1977).PubMedGoogle Scholar
  56. 56.
    J. Ludwig, K. P. Batts, T. P. Moyer, W. P. Baldus, and V. F. Fairbanks, Liver biopsy diagnosis of homozygous hemochromatosis: a diagsotic algorithm,Mayo Clin. Proc. 68, 263–267 (1993).PubMedGoogle Scholar
  57. 57.
    W. H. Crosby, Hemochromatosis: The unsolved problems,Semin. Hematol. 14, 135–143 (1977).PubMedGoogle Scholar
  58. 58.
    G. D. McIaren, W. A. Muir, and R. W. Kellermeyer,CRC Crit Rev. Clin. Lab. Sci. 19, 205–266 (1983).CrossRefGoogle Scholar
  59. 59.
    K. S. Eyres, E. V. McCloskey, E. D. Fern, S. Rogers, M. Beneton, J. E. Aaron, and J. A. Kanis, Osteoporotic fractures: an unusual presentation of haemochromatosis,Bone 13, 431–433 (1992).PubMedCrossRefGoogle Scholar
  60. 60.
    Y. Pawlotsky, M. Simon, Y. Hany, P. Brissot, and M. Bourel, High plasma parathyroid hormone levels and osteo-articular changes in primary haemochromatosis,Scand. J. Rheum. 4, 8 (1975).Google Scholar
  61. 61.
    P. Ross and B. Wood, Osteoarthropathy in idiopathic hemochromatosis,Am. J. Roentgenol. 109, 575–580 (1970).Google Scholar
  62. 62.
    D. Conte, M. P. Caraceni, J. Douriez, C. Mandelli, E. Corghi, M. Cesana, S. Ortolani and P. A. Bianchi, Bone involvement in primary hemochromatosis and alcoholic cirrhosis,Am. J. Gastroenterol. 84, 1231–1234 (1989).PubMedGoogle Scholar
  63. 63.
    H. R. Schumacher Jr., Hemochromatosis and arthritis,Arthritis Rheum. 7, 41–50 (1964).PubMedCrossRefGoogle Scholar
  64. 64.
    L. W. Powell, K. M. Summers, P. G. Board, E. Axelsen, S. Webb, and J. W. Halliday, Expression of hemochromatosis in homozygous subjects. Implications for early diagnosis and prevention,Gastroenterology 98, 1625–1632 (1990).PubMedGoogle Scholar
  65. 65.
    Y. M. Deugnier, O. Loréal, B. Turlin, D. Guyader, H. Jouanolle, R. Moirand, C. Jacquelinet, and P. Brissot, Liver pathology in genetic hemochromatosis: A review of 135 homozygous cases and their bioclinical correlations,Gastroenterology 102, 2050–2059 (1992).PubMedGoogle Scholar
  66. 66.
    M. L. Bassett, J. W. Halliday, S. Bryant, O. Dent, and L. W. Powell, Screening for hemochromatosis,Ann. NY Acad. Sci. 526, 274–289 (1988).PubMedCrossRefGoogle Scholar
  67. 67.
    R. J. Ward, A. L. Florence, D. Baldwin, C. Abiaka, F. Roland, M. H. Ramsey, D. P. E. Dickson, T. J. Peters, and R. R. Crichton, Biochemical and biophysical investigations of the ferrocene-iron-loaded rat. An animal model of primary haemchromatosis,Eur. J. Biochem. 202, 405–410 (1991).PubMedCrossRefGoogle Scholar
  68. 68.
    P. Nielsen and H. C. Heinrich, Metabolism of iron from (3,5,5-trimethylhexanoyl) ferrocene in rats. A dietary model for severe iron overload,Biochem. Pharmacol. 45, 385–391 (1993).PubMedCrossRefGoogle Scholar
  69. 69.
    C. Stitt, P. J. Charley, E. M. Butt, and P. Saltman, Rapid induction of iron deposition in spleen and liver with an iron-fructose chelate,Proc. Soc. Exp. Biol. Med. 110, 70, 71 (1962).PubMedGoogle Scholar
  70. 70.
    G. M. Williams and R. S. Yamamoto, Absence of stainable iron from preneoplastic and neoplastic lesions in rat liver with 8-hydroxyquinoline-induced siderosis, peroral ferrous gluconate,J. Natl. Cancer Inst. 49, 685–692 (1972).PubMedGoogle Scholar
  71. 71.
    P. E. Lisboa, Experimental hepatic cirrhosis in dogs caused by chronic massive iron overload,Gut 12, 363–368 (1971).PubMedCrossRefGoogle Scholar
  72. 72.
    R. A. MacDonald and G. Pechet, Experimental hemochromatosis in rats,Am. J. Pathol. 46, 85–109 (1965).PubMedGoogle Scholar
  73. 73.
    T. D. Kinney, D. M. Hegsted, and C. A. Finch, The influence of diet on iron absorption. I. The pathology of iron excess.J. Exper. Med. 90, 137–146 (1949).CrossRefGoogle Scholar
  74. 74.
    L. A. Goldsmith, Relative magnesium deficiency in the rat,J. Nutr. 93, 87–102 (1967).PubMedGoogle Scholar
  75. 75.
    P. R. Hearn and R. G. G. Russell, Formation of calcium pyrophosphate crystals in vitro: implications for calcium pyrophosphate crystal deposition disease (pseudogout),Ann. Rheum. Dis. 39, 222–227 (1980).PubMedGoogle Scholar
  76. 76.
    G. N. Bowers and R. B. McComb, A continuous spectrophotometric method for measuring the activity of serum alkaline phosphatase,Clin. Chem. 12, 70–89 (1966).PubMedGoogle Scholar
  77. 77.
    H. N. Fernley and P. G. Walker, Studies on alkaline phosphatase: inhibition by phosphate derivatives and the substrate specificity,Biochem. J. 104, 1011–1018 (1967).PubMedGoogle Scholar
  78. 78.
    D. W. Moss, R. H. Eaton, J. K. Smith, et al., Association of inorganic pyrophosphatase activity with human alkaline-phosphatase preparations,Biochem. J. 102, 53–57 (1967).PubMedGoogle Scholar
  79. 79.
    J. D. O'Duffy, Hypophosphatasia associated with calcium pyrophosphate dihydrate deposits in cartilage,Arthritis Rheum. 13, 381–388 (1970).PubMedCrossRefGoogle Scholar
  80. 80.
    D. J. McCarty, P. F. Pepe, S. D. Solomon, and J. Cobb, Inhibition of human erythrocyte pyrophosphatase activity by calcium, cupric and ferrous iron,Arthritis Rheum. 13, 336 (1970) (Abstract).Google Scholar
  81. 81.
    H. Shimada, K. Nakatsuka, T. Miki, Y. Nishizawa, T. Tabata, T. Inoue, and H. Morii, Effect of low magnesium dialysate on the level of parathyroid hormone in patients with chronic renal failure, inMagnesium in Health and Disease, Y. Itokawa and J. Durlach, eds., John Libbey, London, pp. 323–329 (1989).Google Scholar
  82. 82.
    C. S. Anast and L. F. Forte, Parathyroid function and magnesium depletion in the rat,Endocrinology,113, 184–189 (1983).PubMedCrossRefGoogle Scholar
  83. 83.
    A. Doherty, A. Chuck, D. Hosking, and E. Hamilton, Inorganic pyrophosphate in metabolic diseases predisposing to calcium pyrophosphate dihydrate crystal deposition.Arthritis Rheum. 34, 1297–1303 (1991).PubMedCrossRefGoogle Scholar
  84. 84.
    L. Runberg, Y. Coolan, E. J. Jokinen, J. Lähdevirta, and A. Aro, Hypomagnesemia due to renal disease of unknown etiology,Am. J. Med. 59, 873–881 (1975).CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1996

Authors and Affiliations

  • Mieko Kimura
    • 1
  • Katsuhiko Yokoi
    • 1
  1. 1.Department of Social Medicine, Graduate School of MedicineKyoto UniversityKyotoJapan

Personalised recommendations