, Volume 16, Issue 1, pp 9–40 | Cite as

The copper-iron chronicles: The story of an intimate relationship

  • Paul L. Fox


During the last decade there has been a surge of interest and activity in exploring the metabolic links between copper and iron. This review describes more than a century and a half of effort that has led to our current understanding. Particular attention is given to the early events since these are less well-known and appreciated. The landmark 1928 paper of Hart, Elvehjem and coworkers is generally given credit for the start of the copper/iron field, and specifically for the discovery of the role of copper in forming hemoglobin and in overcoming anemia. However, some credit for the ideas, observations, and experiments should be shared with several investigators of the previous century. These scientists and physicians were primarily motivated to find the causes and cures of chlorosis, a common form of anemia at the time. From his chemical determination of copper in red blood cells in 1848, Millon proposed a form of chlorosis due to copper deficiency. Likewise, Pécholier and Saint-Pierre, observing the robust health of young women working in copper factories, concluded that copper was helpful in preventing and overcoming chlorosis. The first direct experimental evidence for the theory was provided by the Italian physician Mendini, who in 1862 reported that supplementation of the diet with copper salts overcame chlorosis in young women. In the 1890s Cervello and his students in Italy, using semi-quantitative hematological measurements, confirmed the beneficial effects of copper on anemia both in patients and in animal models. There was nearly a 30-year period of inactivity, but the decade of the 1930s saw renewed interest and exciting developments in the field. The Elvehjem report of 1928 was quickly verified and extended by multiple laboratories on four continents. In the 1950s and 1960s Wintrobe and Cartwright and their colleagues localized, and started to systematically evaluate, the potential sites at which copper was likely to effect iron for hemoglobin synthesis, namely, intestinal absorption, release from storage, and cellular utilization during synthesis. The copper/iron connection also has a `flip-side', i.e., iron status can influence copper metabolism as first described by Warburg and Krebs in 1927. Thus, there are opportunities for feedback mechanisms at the cellular and physiological level that are not yet understood. The evaluation of these processes continues to this day, aided by modern molecular and genetic approaches. Studies of two copper proteins, ceruloplasmin and its recently discovered homologue hephaestin, have provided two molecular links connecting the pathways of copper and iron metabolism. The recent identification of other proteins of iron and copper metabolism, for example, copper ATPases and the membrane iron transporters DCT1/DMT1/Nramp2 and IREG1/MTP1/ferroportin1, are likely to fill crucial pathway gaps. The ongoing discovery of genes and gene mutations involved in the metabolism of copper and iron provides an important key to a deeper understanding of the connections between the pathways, and their physiological and pathological consequences. It is hoped that this historical review, by illuminating the complex paths that have led to the current state of knowledge, will contribute to our appreciation, our understanding, and perhaps our continued discovery of the connections between copper and iron.

ceruloplasmin hephaestin history of science metabolism nutrition nutrient interaction 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abboud S, Haile DJ. 2000 A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275, 19906-19912.Google Scholar
  2. Abderhalden E. 1899 Assimilation des Eisens. Z Biol 39, 193-270.Google Scholar
  3. Albergoni V, Cassini A. 1975 The oxidation of cysteine by ceruloplasmin. FEBS Lett 55, 261-264.Google Scholar
  4. Anderson GJ, Murphy TL, Cowley L et al. 1998 Mapping the gene for sex-linked anemia: an inherited defect of intestinal iron absorption in the mouse. Genomics 48, 34-39.Google Scholar
  5. Askwith C, Eide D, Van Ho A et al. 1994 The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76, 403-410.Google Scholar
  6. Askwith C, Kaplan J. 1997 An oxidase-permease-based iron transport system in Schizosaccharomyces pombe and its expression in Saccharomyces cerevisiae. J Biol Chem 272, 401-405.Google Scholar
  7. Askwith C, Kaplan J. 1998 Iron and copper transport in yeast and its relevance to human disease. Trends Biochem Sci 23, 135-138.Google Scholar
  8. Attieh ZK, Mukhopadhyay CK, Seshadri V et al. 1999 Ceruloplasmin ferroxidase activity stimulates cellular iron uptake by a trivalent cation-specific transport mechanism. J Biol Chem 274, 1116-1123.Google Scholar
  9. Author anonymous. 1901 Traitement de la chlorose par l'acétate de cuivre. La Semaine Méd Jan. 19, 24.Google Scholar
  10. Baker E, Morton AG, Tavill AS. 1980 The regulation of iron release from the perfused rat liver. Br J Haematol 45, 607-620.Google Scholar
  11. Bannerman RM, Cooper RG. 1966 Sex-linked anemia: a hypochromic anemia of mice. Science 151, 581-582.Google Scholar
  12. Bannerman RM, Pinkerton PH. 1967 X-linked hypochromic anaemia of mice. Br J Haematol 13, 1000-1013.Google Scholar
  13. Barer AP, Fowler WM. 1937 Influence of copper and a liver fraction on retention of iron. Arch Intern Med 60, 474-481.Google Scholar
  14. Bates GW, Workman EF, Jr., Schlabach MR. 1973 Does transferrin exhibit ferroxidase activity? Biochem Biophys Res Commun 50, 84-90.Google Scholar
  15. Baumann H, Gauldie J. 1994 The acute phase response. Immunol Today 15, 74-80.Google Scholar
  16. Beard HH, Myers VC. 1931 Studies in the nutritional anemia of the rat. I. Influence of iron upon blood regeneration. J Biol Chem 94, 71-88.Google Scholar
  17. Beaumier DL, Caldwell MA, Holbein BE. 1984 Inflammation triggers hypoferremia and de novo synthesis of serum transferrin and ceruloplasmin in mice. Infect Immun 46, 489-494.Google Scholar
  18. Bethell FH, Goldhamer SM, Isaacs R et al. 1934 The diagnosis and treatment of the iron-deficiency anemias. JAMA 103, 797-802.Google Scholar
  19. Bing FC, Saurwein EM, Myers VC. 1934 Studies in the nutritional anemia of the rat. X. Hemoglobin production and iron and copper metabolism with milk of low copper content. J Biol Chem 105, 343-354.Google Scholar
  20. Brittin GM, Chee QT. 1969 Relation of ferroxidase (ceruloplasmin) to iron absorption. J Lab Clin Med 74, 53-59.Google Scholar
  21. Broun ER, Greist A, Tricot G et al. 1990 Excessive zinc ingestion. A reversible cause of sideroblastic anemia and bone marrow depression. JAMA 264, 1441-1443.Google Scholar
  22. Burq V. 1852 It Note sur une application des métaux a l'étude et au traitement de la chlorose. Gaz Méd de Paris 450-451.Google Scholar
  23. Burq V. 1853 Métallothérapie. Nouveau It traitment par les applications métalliques. Abrégé. Historique, théorique et pratique. Paris: Germer-Baillière.Google Scholar
  24. Burq V. 1860 La chlorose at la métallothérapie. L'Union Méd 7: 119-122.Google Scholar
  25. Bush JA, Jensen WN, Athens JW et al. 1956 Studies on copper metabolism. XIX. The kinetics of iron metabolism and erythrocyte life-span in copper-deficient swine. J Exp Med 103, 701-712.Google Scholar
  26. Béchamp. 1859 Sur les metaux qui peuvent exister dans le sang ou les viscères, et spécialement sur le cuivre dit physiologique. Montpellier Méd 3, 311-339.Google Scholar
  27. Bédard YC, Pinkerton PH, Simon GT. 1976 Uptake of circulating iron by the duodenum of normal mice and mice with altered iron stores, including sex-linked anemia: high resolution radioautographic study. Lab Invest 34, 611-615.Google Scholar
  28. Caffrey JM, Smith HA, Schmitz JC et al. 1990 Hemolysis of rabbit erythrocytes in the presence of copper ions: inhibition by albumin and ceruloplasmin. Biol Trace Elem Res 25, 11-20.Google Scholar
  29. Cairo G, Conte D, Bianchi L et al. 2001 Reduced serum ceruloplasmin levels in hereditary haemochromatosis. Br J Haematol 114, 226-229.Google Scholar
  30. Cartwright GE, Lauritsen MA, Jones PJ et al. 1946 The anemia of infection. I. Hypoferremia, hypercupremia, and alterations in porphyrin metabolism in patients. J Clin Invest 25, 65-80.Google Scholar
  31. Cartwright GE, Hughley OM, Ashenbrucker H et al. 1948 Studies on free erythrocyte protoporphyrin, plasma iron and plasma copper in normal and anaemic subjects. Blood 3, 501-525.Google Scholar
  32. Cartwright GE, Gubler CJ, Bush JA et al. 1956 Studies on copper metabolism. XVII. Further observations on the anemia of copper deficiency in swine. Blood 11, 143-153.Google Scholar
  33. Castronuovo G. 1895 Azione del Rame sul sangre e sul ricambio materiale. Il Progresso Med 9, 236-248.Google Scholar
  34. Cervello V. 1894 Sul potere ematogeno dei metalli pesanti. Nota I. Influenza del rame nelle anemie. Arch di Farmacol e Terap 2, 481-489.Google Scholar
  35. Cervello V. 1901 Les métaux pesants, considérés comme médicaments hématogènes dans le traitement de l'anémie. J des Praticiens 22-24.Google Scholar
  36. Cervello V, Barabini E. 1894 Sul potere ematogeno dei metalli pesanti. Palermo: Tipografia editrice Tempo.Google Scholar
  37. Chabanier H, Rollln L, Chabanier E. 1913 Action du cuivre colloidal sur le sang. La Presse Méd 21, 102-103.Google Scholar
  38. Chase MS, Gubler CJ, Cartwright GE et al. 1952 Studies on copper metabolism. IV. The influence of copper on the absorption of iron. J Biol Chem 199, 757-763.Google Scholar
  39. Chevallier A, Boys de Loury. 1848 Memoire sur les ouvriers qui travaillent le cuivre et ses alliages. Ann d'Hygiène Pub et de Méd Lég 43, 369.Google Scholar
  40. Chevallier A, Cottereau E. 1849 Essais historiques sur les métaux que l'on rencontre quelquefois dans les corps organisés. Ann d'Hygiène Pub et de Méd Lég 41, 387-425.Google Scholar
  41. Cohen E, Elvehjem CA. 1934 The relation of iron and copper to the cytochrome and oxidase content of animal tissues. J Biol Chem 106, 735-744.Google Scholar
  42. Cohn EJ. 1947 Chemical, physiological, and immunological properties and clinical uses of blood derivatives. Experientia 3, 125-168.Google Scholar
  43. Cook SF, Spilles NM. 1931 Some factors regulating the utilization of splenic iron. Am J Physiol 98, 626-635.Google Scholar
  44. Coppen DE, Davies NT. 1988 Studies on the roles of apotransferrin and caeruloplasmin (EC on iron absorption in copper-deficient rats using an isolated vascularly-and luminallyperfused intestinal preparation. Br J Nutr 60, 361-373.Google Scholar
  45. Cordano A, Baertl JM, Graham GG. 1964 Copper deficiency in infancy. Pediatrics 34, 324-336.Google Scholar
  46. Cox DW. 1966 Factors influencing serum ceruloplasmin levels in normal individuals. J Lab Clin Med 68, 893-904.Google Scholar
  47. Craven CM, Alexander J, Eldridge M, et al. 1987 Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. Proc Natl Acad Sci USA 84, 3457-3461.Google Scholar
  48. Crichton RR, Pierre JL. 2001 Old iron, young copper: from Mars to Venus. Biometals 14, 99-112.Google Scholar
  49. Cunningham IJ. 1931 CXLI. Some biochemical and physiological aspects of copper in animal nutrition. Biochem J 25, 1267-1294.Google Scholar
  50. Curzon G. 1961 Some properties of coupled iron-caeruloplasmin oxidation systems. Biochem J 79, 656-663.Google Scholar
  51. Curzon G, O'Reilly S. 1960 A coupled iron-caeruloplasmin oxidation system. Biochem Biophys Res Commun 2, 284-286.Google Scholar
  52. Dallman PR, Goodman JR. 1970 Enlargement of mitochondrial compartment in iron and copper deficiency. Blood 35, 496-505.Google Scholar
  53. Dancis A, Yuan DS, Haile D et al. 1994 Molecular characterization of a copper transport protein in S. cerevisiae: An unexpected role for copper in iron transport. Cell 76, 393-402.Google Scholar
  54. Dollwet HH, Sorenson JR. 1985 Historic uses of copper compounds in medicine. Trace Elem Med 2, 80-87.Google Scholar
  55. Donovan A, Brownlie A, Zhou Y, et al. 2000 Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776-781.Google Scholar
  56. Dunlap WM, James GW, Hume DM. 1974 Anemia and neutropenia caused by copper deficiency. Ann Intern Med 80, 470-476.Google Scholar
  57. Edwards CQ, Williams DM, Cartwright GE. 1979 Hereditary hypoceruloplasminemia. Clin Genet 15, 311-316.Google Scholar
  58. Elvehjem CA. 1935 The biological significance of copper and its relation to iron metabolism. Physiol Rev 15, 471-507.Google Scholar
  59. Elvehjem CA, Hart EB. 1929 The relation of iron and copper to hemoglobin synthesis in the chick. J Biol Chem 84, 131-141.Google Scholar
  60. Elvehjem CA, Hart EB. 1932 The necessity of copper as a supplement to iron for hemoglobin formation in the pig. J Biol Chem 95, 363-370.Google Scholar
  61. Elvehjem CA, Sherman WC. 1932 The action of copper in iron metabolism. J Biol Chem 98, 309-319.Google Scholar
  62. Elvehjem CA, Steenbock H, Hart EB. 1929 Is copper a constituent of the hemoglobin molecule? The distribution of copper in blood. J Biol Chem 83, 21-25.Google Scholar
  63. Elvehjem CA, Siemers A, Mendenhall DR. 1935 Effect of iron and copper therapy on hemoglobin content of the blood of infants. Am J Dis Child 50, 28-35.Google Scholar
  64. Erel O. 1998 Automated measurement of serum ferroxidase activity. Clin Chem 44, 2313-2319.Google Scholar
  65. Falconer DS, Isaacson JH. 1962 The genetics of sex-linked anaemia in the mouse. Genet Res Cambr 3, 248-250.Google Scholar
  66. Fay J, Cartwright GE, Wintrobe MM. 1949 Studies on free erythrocyte protoporphyrin, serum iron, serum iron-binding capacity and plasma copper during normal pregnancy. J Clin Invest 28, 487-491.Google Scholar
  67. Felletár E. 1908 Czukrászati crémes sütemének okozta, rézmérgezésnek vélt megbetegedési esetek. Gyogyaszat 48, 466-469.Google Scholar
  68. Frazer DM, Vulpe CD, McKie AT, et al. 2001 Cloning and gastrointestinal expression of rat hephaestin: relationship to other iron transport proteins. Am J Physiol 281, G931-G939.Google Scholar
  69. Goodman JR, Dallman PR. 1969 Role of copper in iron localization in developing erythrocytes. Blood 34, 747-753.Google Scholar
  70. Gorter E. 1933 Copper and anemia. Am J Dis Child 46, 1066-1074.Google Scholar
  71. Graham GG, Cordano A. 1969 Copper depletion and deficiency in the malnourished infant. Johns Hopkins Med J 124, 139-150.Google Scholar
  72. Gorter E, Grendel F. 1925 On bimolecular layers of lipoids on the chromocytes of the blood. J ExpMed 41, 439-443.Google Scholar
  73. Gorter E, Grendel F, Weyers WA. 1931 De rol van het koper bij de kinderanaemie. Maandschr V Kindergeneesk 1, 70-86.Google Scholar
  74. Grewal MS. 1963 A sex-linked anaemia in the mouse. Genet Res Cambr 3, 238-247.Google Scholar
  75. Guagenti S. 1896 Sul potere ematogeno dei metalli pesanti. Arch di Farmacol e Terap 4, 361-372.Google Scholar
  76. Gubler CJ, Lahey ME, Chase MS et al. 1952 Studies on copper metabolism. III. The metabolism of iron in copper deficient swine. Blood 7, 1075-1092.Google Scholar
  77. Hare HA. 1892 The treatment of anaemia by copper and arsenic. Therapeut Gaz 16, 30-31.Google Scholar
  78. Harris ED. 1995 The iron-copper connection: the link to ceruloplasmin grows stronger. Nutr Rev 53, 170-173.Google Scholar
  79. Harris ZL, Klomp LW, Gitlin JD. 1998 Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Am J Clin Nutr 67, 972S-977S.Google Scholar
  80. Harris ZL, Durley AP, Man TK et al. 1999 Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA 96, 10812-10817.Google Scholar
  81. Hart EB, Steenbock H, Elvehjem CA, et al. 1925 Iron in nutrition. I. Nutritional anemia on whole milk diets and the utilization of inorganic iron in hemoglobin building. J Biol Chem 65, 67-80.Google Scholar
  82. Hart EB, Steenbock H, Waddell J et al. 1928 Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Biol Chem 77, 797-812.Google Scholar
  83. Hart EB, Steenbock H, Waddell J et al. 2001 Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Trace Elements Exp Med 14, 195-206.Google Scholar
  84. Hendrych F, Mori S. 1933 Die Bedingungen der Oxydation des Eisens im Blute. Arch Exp Path Pharmakol 172, 1-4.Google Scholar
  85. Holmberg CG. 1944 On the presence of a laccase-like enzyme in serum and its relation to the copper in serum. Acta Physiol Scand 8, 227-229.Google Scholar
  86. Holmberg CG, Laurell C-B. 1947 Investigations in serum copper. I. Nature of serum copper and its relation to the iron-binding protein in human serum. Acta Chem Scand 1, 944-950.Google Scholar
  87. Holmberg CG, Laurell C-B. 1948 Investigations in serum copper. II. Isolation of the copper containing protein, and a description of some of its properties. Acta Chem Scand 2, 550-556.Google Scholar
  88. Holmberg CG, Laurell C-B. 1951 Oxidase reactions in human plasma caused by coeruloplasmin. Scand J Lab Clin Invest 3, 103-107.Google Scholar
  89. Houk AE, Thomas AW, Sherman HC. 1946 Some interrelationships of dietary iron, copper and cobalt in metabolism. J Nutr 31, 609-619.Google Scholar
  90. Hutchison JH. 1938 The role of copper in iron-deficiency anaemia in infancy. Q JMed 7, 397-419.Google Scholar
  91. Inman RS, Coughlan MM, Wessling-Resnick M. 1994 Extracellular ferrireductase activity of K562 cells is coupled to transferrinindependent iron transport. Biochemistry 33, 11850-11857.Google Scholar
  92. Iwanska S, Strusinska D. 1978 Copper metabolism in different states of erythropoiesis activity. Acta Physiol Pol 29, 465-474.Google Scholar
  93. Johnson DA, Osaki S, Frieden E. 1967 A micromethod for the determination of ferroxidase (ceruloplasmin) in human serums. Clin Chem 13, 142-150.Google Scholar
  94. Johnson MA, Hove SS. 1986 Development of anemia in copperdeficient rats fed high levels of dietary iron and sucrose. J Nutr 116, 1225-1238.Google Scholar
  95. Johnson MA, Murphy CL. 1988 Adverse effects of high dietary iron and ascorbic acid on copper status in copper-deficient and copper-adequate rats. Am J Clin Nutr 47, 96-101.Google Scholar
  96. Josephs H. 1931 Treatment of anaemia of infancy with iron and copper. Bull Johns Hopkins Hosp 49, 246-258.Google Scholar
  97. Josephs HW. 1932 Studies on iron metabolism and the influence of copper. J Biol Chem 96, 559-571.Google Scholar
  98. Kalra R, Kalra VB, Sareen PM, et al. 1989 Serum copper and ceruloplasmin in pregnancy with anaemia. Indian J Pathol Microbiol 32, 28-32.Google Scholar
  99. Kaplan J. 1996 Metal transport and unsafe sanctuary sites. J Clin Invest 98, 3-4.Google Scholar
  100. Kaplan J, O'Halloran TV. 1996 Iron metabolism in eukaryotes: Mars and Venus at it again. Science 271, 1510-1512.Google Scholar
  101. Karpel JT, Peden VH. 1972 Copper deficiency in long-term parenteral nutrition. J Pediatr 80, 32-36.Google Scholar
  102. Keil HL, Nelson VE. 1931 The rôle of copper in hemoglobin regeneration and in reproduction. J Biol Chem 93, 49-57.Google Scholar
  103. Klevay LM. 1997 Paper 10: copper as a supplement to iron for hemoglobin building in the rat (Hart et al. 1928). J Nutr 127, 1034S-1036S.Google Scholar
  104. Klevay LM. 2001 Iron overload can induce mild copper deficiency. J Trace Elem Med Biol 14, 237-240.Google Scholar
  105. Kobert R. 1895 Ueber den jetzigen Stand der Frage nach den pharmakologischen Wirkungen des Kupfers. Deutsche Med Wochen 5, 42-45.Google Scholar
  106. Koechlin BA. 1952 Preparation and properties of serum and plasma proteins. XXVIII. The β1-metal-combining protein of human plasma. J Am Chem Soc 74, 2649-2653.Google Scholar
  107. Koschinsky ML, Funk WD, van Oost BA et al. 1986 Complete cDNA sequence of human preceruloplasmin. Proc Natl Acad Sci USA 83, 5086-5090.Google Scholar
  108. Krauss WE. 1929 Studies on the nutritive value of milk. II. The supplementary value of inorganic iron and copper. J Dairy Sci 12, 242-251.Google Scholar
  109. Krauss WE. 1931 The ineffectiveness of manganese in nutritional anemia. J Biol Chem 90, 267-277.Google Scholar
  110. Kuwatsuru Y. 1961 Studies on the hematopoietic factor ceruloplasmin. Showa Med J 21, 592-605.Google Scholar
  111. Lahey ME, Gubler CJ, Chase MS et al. 1952 Studies on copper metabolism. II. Hematologic manifestations of copper deficiency in swine. Blood 7, 1053-1074.Google Scholar
  112. Lahey ME, Gubler CJ, Cartwright GE et al. 1953 Studies on copper metabolism. VII. Blood copper in pregnancy and various pathologic states. J Clin Invest 32, 329-339.Google Scholar
  113. Lainé F, Ropert M, Le Lan C et al. 2002 Serum ceruloplasmin and ferroxidase activity are decreased in HFE C282Y homozygote male iron-overloaded patients. J Hepatol 36, 60-65.Google Scholar
  114. Lee GR, Cartwright GE, Wintrobe MM. 1968a Heme biosynthesis in copper deficient swine. Proc Soc Exp Biol Med 127, 977-981.Google Scholar
  115. Lee GR, Nacht S, Lukens JN, et al. 1968b Iron metabolism in copper-deficient swine. J Clin Invest 47, 2058-2069.Google Scholar
  116. Levi G, Barduzzi D. 1877a Di alcune applicazioni terapeutiche poco note del solfato di rame. Ricerche sperimentali e cliniche. Parte prima. Giorn di Anat Fisiol e Patol degli Animali 9, 284-294.Google Scholar
  117. Levi G, Barduzzi D. 1877b Di alcune applicazioni terapeutiche poco note del solfato di rame. Ricerche sperimentali e cliniche. Parte seconda. Giorn di Anat Fisiol e Patol degli Animali 9, 337-352.Google Scholar
  118. Levy JE, Jin O, Fujiwara Y et al. 1999 Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nature Genet 21, 396-399.Google Scholar
  119. Levy JE, Montross LK, Andrews NC. 2000 Genes that modify the hemochromatosis phenotype in mice. J Clin Invest 105, 1209-1216.Google Scholar
  120. Levy Y, Zeharia A, Grunebaum M et al. 1985 Copper deficiency in infants fed cow milk. J Pediatr 106: 786-788.Google Scholar
  121. Lewis GT, Weichselbaum TE, McGhee JL. 1930 Effect of metals purified by electrolytic deposition on hemoglobin regeneration in anaemic white rat. Proc Soc Exp Biol Med 27, 329-331.Google Scholar
  122. Lewis MS. 1931 Iron and copper in the treatment of anemia in children. JAMA 96, 1135-1138.Google Scholar
  123. Lindley PF, Card G, Zaitseva I et al. 1997 An X-ray structural study of human ceruloplasmin in relation to ferroxidase activity. J Biol Inorg Chem 2, 454-463.Google Scholar
  124. Liégeois C. 1891 Fer et chlorose. Remarques pratiques sur le choix et le mode d'administration des meilleures préparations ferrugineuses. Rev Méd de l'Est 23, 545-554.Google Scholar
  125. Liégeois. 1900 Fer, arsenic ou cuivre dans la chlorose. J des Praticiens, 615.Google Scholar
  126. Liégeois. 1901a Historique du traitement de la chlorose pars les sels de cuivre. Bull Acad Med Natl 45, 492-498.Google Scholar
  127. Liégeois. 1901b Préparations cupriques pour l'usage interne. J des Praticiens 2-7.Google Scholar
  128. Logan JI, Harveyson KB, Wisdom GB et al. 1994 Hereditary caeruloplasmin deficiency, dementia and diabetes mellitus. Q J Med 87, 663-670.Google Scholar
  129. Loudon IS. 1980 Chlorosis, anaemia, and anorexia nervosa. Br Med J 281, 1669-1675.Google Scholar
  130. Loudon I. 1984 The diseases called chlorosis. Psychol Med 14, 27-36.Google Scholar
  131. Lovstad RA. 1981 The protective effect of ceruloplasmin on Fe2+ stimulated lysis of rat erythrocytes. Int J Biochem 13, 221-224.Google Scholar
  132. Luton A. 1885 De L'acetate de cuivre en thérapeutique. Union Méd et Scient du Nord-Est 9, 317-330.Google Scholar
  133. Mainero A, Aguilar A, Rodarte B et al. 1996 Rabbit ceruloplasmin: Purification and partial characterization. Prep Biochem Biotechnol 26, 217-228.Google Scholar
  134. Manis J. 1970 Active transport of iron by intestine: selective genetic defect in the mouse. Nature 227, 385-386.Google Scholar
  135. Manis J, Schwartz IL. 1973 Ferrous iron oxidation by intestinal mucosa: possible role in mucosal iron metabolism. Proc Soc Exp Biol Med 144, 1025-1029.Google Scholar
  136. Mann T, Keilin D. 1938 Haemocuprein and hepatocuprein, copper protein compounds of blood and liver in mammals. Proc Roy Soc London B 126, 303-315.Google Scholar
  137. Markowitz H, Gubler CJ, Mahoney JP et al. 1955 Studies on copper metabolism. XIV. Copper, ceruloplasmin and oxidase activity in sera of normal human subjects, pregnant women, and patients with infection, hepatolenticular degeneration and the nephrotic syndrome. J Clin Invest 34, 1498-1508.Google Scholar
  138. Marston HR, Allen SH. 1967 Function of copper in the metabolism of iron. Nature 215, 645-646.Google Scholar
  139. McHargue JS, Healy DJ, Hill ES. 1928 The relation of copper to the hemoglobin content of rat blood. J Biol Chem 78, 637-641.Google Scholar
  140. McKie AT, Marciani P, Rolfs A et al. 2000 A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5, 299-309.Google Scholar
  141. McKie AT, Barrow D, Latunde-Dada GO et al. 2001 An ironregulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755-1759.Google Scholar
  142. Melsens. 1848 De l'absence du cuivre et du plomb dans le sang. Annales de Chim et de Phys 23, 358-371.Google Scholar
  143. Mendini L. 1862 Di un rimedio per l'amenorrea et di altro per la sordita ipostenica. Gazz Med Ital Prov Venete 5, 36-37.Google Scholar
  144. Mercadante F. 1897 Studio comparativo sul potere ematogeno di alcuni e di alcuni metalli pesanti. Arch di Farmacol e Terap 5, 521-539.Google Scholar
  145. Millon E. 1848 De la présence normale de plusiers métaux dans le sang de l'homme, et de l'analyse des sels fixes contenus dans ce liquide. Comptes Rend de l'Acad des Sci à Paris 26, 41-43.Google Scholar
  146. Mills ES. 1930 The treatment of idiopathic (hypochromic) anaemia with iron and copper. Can Med Assoc J 22, 175-178.Google Scholar
  147. Miyajima H, Nishimura Y, Mizoguchi K et al. 1987 Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 37, 761-767.Google Scholar
  148. Montosig, Donovan A, Totaro A et al. 2001 Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108, 619-623.Google Scholar
  149. Morais MB, Fisberg M, Suzuki HU, et al. 1994 Effects of oral iron therapy on serum copper and serum ceruloplasmin in children. J Trop Pediatr 40, 51-52.Google Scholar
  150. Morimoto A, Murakami N, Takada M et al. 1987 Fever and acute phase response induced in rabbits by human recombinant interferon-gamma. J Physiol 391, 209-218.Google Scholar
  151. Morita H, Ikeda S, Yamamoto K et al. 1995 Hereditary ceruloplasmin deficiency with hemosiderosis: A clinicopathological study of a Japanese family. Ann Neurol 37, 646-656.Google Scholar
  152. Mukhopadhyay CK, Attieh ZK, Fox PL. 1998 Role of ceruloplasmin in cellular iron uptake. Science 279, 714-717.Google Scholar
  153. Mukhopadhyay CK, Mazumder B, Fox PL. 2000 Role of hypoxia inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 275, 21048-21054.Google Scholar
  154. Muntwyler E, Hanzal RF. 1933 Action of copper and other elements in iron metabolism. Proc Soc Exp Biol Med 30, 845-846.Google Scholar
  155. Murray WW. 1885 Copper as a restorative. Southern Clin 8, 172-1885.Google Scholar
  156. Myers VC, Beard HH. 1931 Studies in the nutritional anemia of the rat. II. Influence of iron plus supplements of other inorganic elements upon blood regeneration. J Biol Chem 94, 89-110.Google Scholar
  157. Njajou OT, Vaessen N, Joosse M, et al. 2001 A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 28, 213-214.Google Scholar
  158. No Author. 1987 Nutrition classics. The Journal of Biological Chemistry, Vol. LXXVII, 1928 PP797-812: Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. By EB Hart, H Steenbock, J Waddell and CA Elvehjem. Nutr Rev 45, 181-183.Google Scholar
  159. Osaki S, Johnson DA. 1969 Mobilization of liver iron by ferroxidase (ceruloplasmin). J Biol Chem 244, 5757-5765.Google Scholar
  160. Osaki S, Kaya T, Kanazawa T et al. 1961 Investigation on ceruloplasmin. II. Crystallization of porcine ceruloplasmin. Proc Jpn Acad 37, 54-56.Google Scholar
  161. Osaki S, Johnson DA, Frieden E. 1966 The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 241, 2746-2751.Google Scholar
  162. Osaki S, Johnson DA, Frieden E. 1971 The mobilization of iron from the perfused mammalian liver by a serum copper enzyme, ferroxidase I. J Biol Chem 246, 3018-3023.Google Scholar
  163. Pagliardi E, Giangrandi E, Vinti A. 1957 Compartamento del rame plasmatico ed eritrocitario in condizioni morbose. Rass Fisiopatol Clin Terap 29, 907-921.Google Scholar
  164. Parsons LG. 1933 The deficiency anaemias of childhood. Br Med J 2, 631-636.Google Scholar
  165. Patel BN, David S. 1997 A novel glycosylphosphatidylinositolanchored form of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem 272, 20185-20190.Google Scholar
  166. Patterson WP, Winkelmann M, Perry MC. 1985 Zinc-induced copper deficiency: Megamineral sideroblastic anemia. Ann Intern Med 103, 385-386.Google Scholar
  167. Pedersen JZ, Franck C. 1987 Increased serum levels of ceruloplasmin in severe chronic airflow obstruction. Eur J Respir Dis 70, 140-144.Google Scholar
  168. Peppriell JE, Edwards JA, Bannerman RM. 1982 The kinetics of iron uptake by isolated intestinal cells from normal mice and mice with sex-linked anemia. Blood 60, 635-641.Google Scholar
  169. Perron. 1861 Des maladies des horlogers produits par le cuivre et l'absorption des molécules cuivreuses. Ann d'Hygiène 16, 70-104.Google Scholar
  170. Pinkerton PH, Bannerman RM. 1967 Hereditary defect in iron absorption in mice. Nature 216, 482-483.Google Scholar
  171. Pinkerton PH. 1968 Histological evidence of disordered iron transport in the X-linked hypochromic anaemia of mice. J Pathol Bacteriol 95, 155-165.Google Scholar
  172. Potter VR, Elvehjem CA, Hart EB. 1938 Anemia studies with dogs. J Biol Chem 126, 155-173.Google Scholar
  173. Prasad AS, Brewer GJ, Schoomaker EB et al. 1978 Hypocupremia induced by zinc therapy in adults. JAMA 240, 2166-2168.Google Scholar
  174. Pécholier G, Saintpierre C. 1864 Étude sur L'hygiène des ouvriers employés a la fabrication du verdet. Montpellier Méd 12, 97-127.Google Scholar
  175. Qian ZM, Ke Y. 2001 Rethinking the role of ceruloplasmin in brain iron metabolism. Brain Res Rev 35, 287-294.Google Scholar
  176. Qian ZM, Tsoi YK, Ke Y et al. 2001 Ceruloplasmin promotes iron uptake rather than release in BT325 cells. Exp Brain Res 140, 369-374.Google Scholar
  177. Racker E. 1965 Mechanisms in bioenergetics. New York: Academic Press.Google Scholar
  178. Rademacher JG. 1848 Rechtfertigung der von den Gelehrten mifkannten, verstandesrechten Erfahrungsheillehre. Berlin: Druck und Verlag von G. Reimer.Google Scholar
  179. Ragan HA, Nacht S, Lee GR, et al. 1969 Effect of ceruloplasmin on plasma iron in copper-deficient swine. Am J Physiol 217, 1320-1323.Google Scholar
  180. Richardson DR. 1999 Role of ceruloplasmin and ascorbate in cellular iron release. J Lab Clin Med 134, 454-465.Google Scholar
  181. Robb-Smith AH. 1933 The history of the hedgehog's rosary. St Bartholomew's Hosp J 40, 149-152, 166-168, 211-216, 238- 240; 41, 13-15.Google Scholar
  182. Roeser HP, Lee GR, Nacht S et al. 1970 The role of ceruloplasmin in iron metabolism. J Clin Invest 49, 2408-2417.Google Scholar
  183. Rydén L. 1984 Ceruloplasmin. In: Lontie R. (ed.): Copper proteins and copper enzymes, volume III. Boca Raton, FL: CRC Press; 37-100.Google Scholar
  184. Sachs A. 1938 The effect of bleeding ulcers and hemorrhagic anemia upon whole blood copper and iron. Am J Digest Dis Nutr 4, 803-804.Google Scholar
  185. Saenko EL, Yaropolov AI. 1990 The protective effect of different forms of human ceruloplasmin in copper-induced lysis of red blood cells. Biochem Int 22, 57-66.Google Scholar
  186. Sarata U. 1934 Studies in the biochemistry of copper. III. Distribution of copper between the corpuscles and plasma. Jap JMed Sci II, Biochem 2, 305-307.Google Scholar
  187. Sarata U, Suzuki A. 1934 Studies in the biochemistry of copper. V. Effect of rapid loss of blood upon the copper content of blood. Jap J Med Sci II, Biochem 2, 341-354.Google Scholar
  188. Sarzeau. 1830 Sur la présence dans les végétaux et dans le sang. Bull Travaux Soc Pharm 505-518.Google Scholar
  189. Scarpinato G. 1895 Sul potere ematogeno del cupro-emolo. Arch di Farmacol e Terap 3, 557-568.Google Scholar
  190. Schade AL, Caroline L. 1944 Raw hen egg white and the role of iron in growth inhibition of Shigella dysenteriae, Stapylococcus aureus, Escherichia coli and Saccharomyces cerevisiae. Science 100, 14-15.Google Scholar
  191. Schade AL, Caroline L. 1946 An iron-binding component in human blood plasma. Science 104, 340-341.Google Scholar
  192. Scheinberg IH, Gitlin D. 1952 Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease). Science 116, 484-485.Google Scholar
  193. Schultze MO. 1940 Metallic elements and blood formation. Physiol Rev 20, 37-67.Google Scholar
  194. Schultze MO. 1941 The relation of copper to cytochrome oxidase and hematopoietic activity of the bone marrow of rats. J Biol Chem 138, 219-224.Google Scholar
  195. Schultze MO, Elvehjem CA. 1933 The relation of iron and copper to the reticulocyte response in anemic rats. J Biol Chem 102, 357-371.Google Scholar
  196. Schultze MO, Elvehjem CA, Hart EB. 1934 The availability of copper in various compounds as a supplement to iron in hemoglobin formation. J Biol Chem 106, 735-744.Google Scholar
  197. SenGupta S, Wehbe C, Majors AK et al. 2001 Relative roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine-cysteine mixed disulfide and cystine in circulation. J Biol Chem 276, 46896-46904.Google Scholar
  198. Shimizu M. 1979 Clinical results on the use of human ceruloplasmin in aplastic anemia. Transfusion 19, 742-748.Google Scholar
  199. Shokeir MH. 1972 Is ceruloplasmin a physiological ferroxidase? Clin Biochem 5, 115-120.Google Scholar
  200. Smith SE, Medlicott M. 1944 The blood picture of iron and copper deficiency anemias in the rat. Am J Physiol 141, 354-358.Google Scholar
  201. Soyars KE, Fischer JG. 1998 Iron supplementation does not affect cell proliferation or aberrant crypt foci development in the colon of Sprague-Dawley rats. J Nutr 128, 764-770.Google Scholar
  202. Spiegel JE, Willenbucher RF. 1999 Rapid development of severe copper deficiency in a patient with Crohn's disease receiving parenteral nutrition. J Parenter Enteral Nutr 23, 169-172.Google Scholar
  203. Starkenstein E, Harvalik Z. 1933 Ñber eine im intermediären Eisenstoffwechsel entstehende Ferriglobulinverbindung. Arch Exp Path Pharmakol 172, 75-92.Google Scholar
  204. Starobinski J. 1981 Chlorosis - the 'green sickness'. Psychol Med 11, 459-468.Google Scholar
  205. Stearman R, Yuan DS, Yamaguchi-Iwai Y et al. 1996 A permeaseoxidase complex involved in high-affinity iron uptake in yeast. Science 271, 1552-1557.Google Scholar
  206. Stein HB, Lewis RC. 1933 The stimulating action of copper on erythropoiesis. J Nutr 6, 465-472.Google Scholar
  207. Surks MI. 1966 Elevated PBI, free thyroxine, and plasma protein concentration in man at high altitude. J Appl Physiol 21, 1185-1190.Google Scholar
  208. Takahashi N, Ortel TL, Putnam FW. 1984 Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule. Proc Natl Acad Sci USA 81, 390-394.Google Scholar
  209. Taylor JE, Belch JJ, Fleming LW et al. 1994 Erythropoietin response and route of administration. Clin Nephrol 41, 297-302.Google Scholar
  210. Turner G. 1839 On the effects of certain preparations of copper on the health of persons employed in imitative gilding. Med Gaz 697-702.Google Scholar
  211. Underhill FA, Orten JM, Lewis RC. 1931 The inability of metals other than copper to supplement iron in curing the nutritional anemia of rats. J Biol Chem 91, 13-25.Google Scholar
  212. Van Wyk JJ, Baxter JH, Akeroyd JH et al. 1953 The anemia of copper deficiency in dogs compared with that produced by iron deficiency. Bull Johns Hopkins Hosp 93, 41-49.Google Scholar
  213. Venakteshwara Rao M, Khanijo SK, Chande RD et al. 1975 Serum ceruloplasmin in iron deficiency anaemia. J Assoc Physicians India 23, 571-576.Google Scholar
  214. von Linden M. 1933 Reichsgesetzblatt.Google Scholar
  215. von Linden M. 1935 Das Kupfer in seiner biologischen und therapeutischen Bedeutung. Schweiz Med Wochenschr 29, 660-662.Google Scholar
  216. Vulpe CD, Kuo YM, Murphy TL et al. 1999 Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nature Genet 21, 195-199.Google Scholar
  217. Waddell J, Elvehjem CA, Steenbock H et al. 1928 Iron in nutrition. VI. Iron salts and iron-containing ash extracts in the correction of anemia. J Biol Chem 77, 775-795.Google Scholar
  218. Waddell J, Steenbock H, Hart EB. 1929 Iron in nutrition. X. The specificity of copper as a supplement to iron in the cure of nutritional anemia. J Biol Chem 84, 115-130.Google Scholar
  219. Warburg O. 1927 Methode zur Bestimmung von Kupfer und Eisen und über Kupfergehalt des Blutserums. Biochem Z 187, 255-271.Google Scholar
  220. Warburg O, Krebs HA. 1927 Ñber locker gebundenes Kupfer und Eisen im Blutserum. Biochem Z 190, 143-149.Google Scholar
  221. Williams DM, Loukopoulos D, Lee GR et al. 1976 Role of copper in mitochondrial iron metabolism. Blood 48, 77-85.Google Scholar
  222. Williams DM, Barbuto AJ, Atkin CL et al. 1978 Evidence for an iron carrier substance in copper-deficient mitochondria. Prog Clin Biol Res 21, 539-549.Google Scholar
  223. Wintrobe mm, Cartwright GE, Lahey ME et al. 1951 The rôle of copper in hemopoiesis. Trans Assoc Am Phys 64, 310-315.Google Scholar
  224. Wolf W. 1898 Ueber den Einfluss von Kupfer-und Zinksalzen auf die Hämoglobinbildung. Z Physiol Chem 26, 442-461.Google Scholar
  225. Wollenberg P, Mahlberg R, Rummel W. 1990 The valency state of absorbed iron appearing in the portal blood and ceruloplasmin substitution. Biometals 3, 1-7.Google Scholar
  226. Yamaguchi A. 1965 Studies on ceruloplasmin: especially on its erythropoietic action. Showa Med J 25, 353-366.Google Scholar
  227. Yamamoto M. 1969 Erythropoietic mechanism by combined use of ceruloplasmin and folic acid. Acta Haematol Jap 32, 366-376.Google Scholar
  228. Young SP, Fahmy M, Golding S. 1997 Ceruloplasmin, transferrin and apotransferrin facilitate iron release from human liver cells. FEBS Lett 411, 93-96.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Paul L. Fox
    • 1
  1. 1.Department of Cell BiologyThe Lerner Research Institute, The Cleveland Clinic FoundationClevelandUSA

Personalised recommendations