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. 1970 Dec;49(12):2408–2417. doi: 10.1172/JCI106460

The role of ceruloplasmin in iron metabolism

H P Roeser 1, G R Lee 1, S Nacht 1, G E Cartwright 1
PMCID: PMC322742  PMID: 5480864

Abstract

The importance of ceruloplasmin in iron metabolism was studied in swine made hypoceruloplasminemic by copper deprivation. When the plasma ceruloplasmin level fell below 1% of normal, cell-to-plasma iron flow became sufficiently impaired to cause hypoferremia, even though total body iron stores were normal. When ceruloplasmin was administered to such animals, plasma iron increased immediately and continued to rise at a rate proportional to the logarithm of the ceruloplasmin dose. The administration of inorganic copper induced increases in plasma iron only after ceruloplasmin appeared in the circulation. Thus, ceruloplasmin appeared to be essential to the normal movement of iron from cells to plasma.

Studies designed to define the mechanism of action of ceruloplasmin were based on the in vitro observation that ceruloplasmin behaves as an enzyme (ferroxidase) that catalyzes oxidation of ferrous iron. Retention of injected ferrous iron in the plasma of ceruloplasmin-deficient swine was significantly less than that of ferric iron, reflecting impaired transferrin iron binding. Rat ceruloplasmin, which has little ferroxidase activity, was much less effective than porcine or human ceruloplasmin in inducing increases in plasma iron. These observations suggest that ceruloplasmin acts by virtue of its ferroxidase activity.

Eight patients with Wilson's disease were evaluated in order to investigate iron metabolism in a disorder characterized by reduced ceruloplasmin levels. Evidence of iron deficiency was found in six of these, and in five of the six, plasma ceruloplasmin was less than 5% of normal. In comparison, the two patients without evidence of iron deficiency had ceruloplasmin levels of 11 and 18% of normal. It is suggested that iron deficiency tends to occur in those patients with Wilson's disease who have the severest degrees of hypoceruloplasminemia, possibly because of defective transfer of iron from intestinal mucosal cells to plasma.

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Selected References

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  1. BUSH J. A., JENSEN W. N., ATHENS J. W., ASHENBRUCKER H., CARTWRIGHT G. E., WINTROBE M. M. Studies on copper metabolism. XIX. The kinetics of iron metabolism and erythrocyte life-span in copper-deficient swine. J Exp Med. 1956 May 1;103(5):701–712. doi: 10.1084/jem.103.5.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. BUSH J. A., JENSEN W. N., CARTWRIGHT G. E., WINTROBE M. M. Blood volume studies in normal and anemic swine. Am J Physiol. 1955 Apr;181(1):9–14. doi: 10.1152/ajplegacy.1955.181.1.9. [DOI] [PubMed] [Google Scholar]
  3. Bates G. W., Billups C., Saltman P. The kinetics and mechanism of iron (3) exchange between chelates and transferrin. I. The complexes of citrate and nitrilotriacetic acid. J Biol Chem. 1967 Jun 25;242(12):2810–2815. [PubMed] [Google Scholar]
  4. CARTWRIGHT G. E., MARKOWITZ H., SHIELDS G. S., WINTROBE M. M. Studies on copper metabolism. XXIX. A critical analysis of serum copper and ceruloplasmin concentrations in normal subjects, patients with Wilson's disease and relatives of patients with Wilson's disease. Am J Med. 1960 Apr;28:555–563. doi: 10.1016/0002-9343(60)90150-9. [DOI] [PubMed] [Google Scholar]
  5. Deiss A., Lee G. R., Cartwright G. E. Hemolytic anemia in Wilson's disease. Ann Intern Med. 1970 Sep;73(3):413–418. doi: 10.7326/0003-4819-73-3-413. [DOI] [PubMed] [Google Scholar]
  6. JENSEN W. N., BUSH J. A., ASHENBRUCKER H., CARTWRIGHT G. E., WINTROBE M. M. The kinetics of iron metabolism in normal growing swine. J Exp Med. 1956 Jan 1;103(1):145–159. doi: 10.1084/jem.103.1.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. LAHEY M. E., GUBLER C. J., CHASE M. S., CARTWRIGHT G. E., WINTROBE M. M. Studies on copper metabolism. II. Hematologic manifestations of copper deficiency in swine. Blood. 1952 Nov;7(11):1053–1074. [PubMed] [Google Scholar]
  8. Lee G. R., Nacht S., Christensen D., Hansen S. P., Cartwright G. E. The contribution of citrate to the ferroxidase activity of serum. Proc Soc Exp Biol Med. 1969 Jul;131(3):918–923. doi: 10.3181/00379727-131-34009. [DOI] [PubMed] [Google Scholar]
  9. Lee G. R., Nacht S., Lukens J. N., Cartwright G. E. Iron metabolism in copper-deficient swine. J Clin Invest. 1968 Sep;47(9):2058–2069. doi: 10.1172/JCI105891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Morell A. G., Irvine R. A., Sternlieb I., Scheinberg I. H., Ashwell G. Physical and chemical studies on ceruloplasmin. V. Metabolic studies on sialic acid-free ceruloplasmin in vivo. J Biol Chem. 1968 Jan 10;243(1):155–159. [PubMed] [Google Scholar]
  11. Morell A. G., Van den Hamer C. J., Scheinberg I. H., Ashwell G. Physical and chemical studies on ceruloplasmin. IV. Preparation of radioactive, sialic acid-free ceruloplasmin labeled with tritium on terminal D-galactose residues. J Biol Chem. 1966 Aug 25;241(16):3745–3749. [PubMed] [Google Scholar]
  12. O'Reilly S., Pollycove M., Bank W. J. Iron metabolism in Wilson's disease. Kinetic studies with iron. Neurology. 1968 Jul;18(7):634–644. doi: 10.1212/wnl.18.7.634. [DOI] [PubMed] [Google Scholar]
  13. Osaki S., Johnson D. A., Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem. 1966 Jun 25;241(12):2746–2751. [PubMed] [Google Scholar]
  14. Osaki S. Kinetic studies of ferrous ion oxidation with crystalline human ferroxidase (ceruloplasmin). J Biol Chem. 1966 Nov 10;241(21):5053–5059. [PubMed] [Google Scholar]
  15. RAVIN H. A. An improved colorimetric enzymatic assay of ceruloplasmin. J Lab Clin Med. 1961 Jul;58:161–168. [PubMed] [Google Scholar]
  16. Ragan H. A., Nacht S., Lee G. R., Bishop C. R., Cartwright G. E. Effect of ceruloplasmin on plasma iron in copper-deficient swine. Am J Physiol. 1969 Nov;217(5):1320–1323. doi: 10.1152/ajplegacy.1969.217.5.1320. [DOI] [PubMed] [Google Scholar]
  17. Shokeir M. H., Shreffler D. C. Cytochrome oxidase deficiency in Wilson's disease: a suggested ceruloplasmin function. Proc Natl Acad Sci U S A. 1969 Mar;62(3):867–872. doi: 10.1073/pnas.62.3.867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. TRINDER P. The improved determination of iron in serum. J Clin Pathol. 1956 May;9(2):170–172. doi: 10.1136/jcp.9.2.170. [DOI] [PMC free article] [PubMed] [Google Scholar]

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