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Gene Review

CP  -  ceruloplasmin (ferroxidase)

Homo sapiens

Synonyms: Ceruloplasmin, Ferroxidase
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Disease relevance of CP

  • A significant correlation was noted between SOA and the number of joints with active synovitis, serum CP, CRP and ESR in RA patients [1].
  • CP-1 mRNA was the predominant CP transcript in a lymphoblastic leukemia cell line, CEM [2].
  • Neuronal CP staining in brain specimens from other neurodegenerative disorders showed a slight but nonsignificant increase vs controls [3].
  • Hyperthyroidism caused an evident increase in SOD and CAT activities and CP level, as well as a decrease in GPx and GR activities [4].
  • CP showed various degrees of positivity in all cases of follicular carcinoma and 19 cases (95%) of papillary carcinoma [5].

Psychiatry related information on CP


High impact information on CP

  • We suggest that the hephaestin protein is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals [9].
  • Magnetic resonance imaging of the liver and basal ganglia showed T2-hypointensity signals associated with parenchymal iron accumulation because of an absence of the ferroxidase activity in ceruloplasmin [10].
  • A biochemical analysis of the patients' serum and a biogenesis study of G969S mutant ceruloplasmin using mammalian cell culture system resulted in the synthesis and secretion of only apoceruloplasmin without any ferroxidase activity [10].
  • The aim of this study was to determine whether chloride channels are modulators of copper incorporation into ceruloplasmin (CP) [11].
  • In this review, special emphasis is given to the structure of the ferroxidase centres with native iron-containing sites, since oxidation of ferrous iron by molecular oxygen takes place in these sites [12].

Chemical compound and disease context of CP


Biological context of CP

  • Oligonucleotide probes constructed according to published amino acid sequences were used to identify cDNA clones encoding human CP [18].
  • The CP gene was mapped to human chromosome 3 by somatic-cell-hybrid analysis and to 3q25 by in situ hybridization; however, sites of hybridization to DNA on other chromosomal sites suggested additional CP-like DNA sequences in the human genome [18].
  • These findings predict that alternative RNA splicing may lead to the differential expression of CP genomic sequences and produce alternate isoforms from a single CP gene in specific tissues [2].
  • Increased iron deposition and lipid peroxidation in the basal ganglia of subjects with hereditary CP deficiency suggest that CP may serve as an anti-oxidant in the brain as well [3].
  • Systemic inflammation and oxidative stress are major factors stimulating hepatic CP synthesis, and it remains to be determined whether increased CP concentrations in AD CSF and brain follow from similar mechanisms [19].

Anatomical context of CP

  • Complex Cp-Lf demonstrating ferroxidase activity was discovered in breast milk [20].
  • CP mRNA was detected in human liver, macrophages, and lymphocytes by in situ histohybridization [18].
  • Neuronal CP staining intensity tended to increase in most AD brain regions, but was statistically significant vs controls only in the CA1 region of hippocampus (p = .016) [3].
  • CP was detected in both neurons and astrocytes in all specimens, and in senile plaques and occasional neurofibrillary tangles in AD brain [3].
  • Upon injection into rat of human LF, the latter is soon revealed within the CP/LF complex of the blood plasma, from where the human protein is substantially cleared within 5 h [21].

Associations of CP with chemical compounds

  • Ceruloplasmin (CP) is a plasma glycoprotein that transports copper throughout the body [2].
  • The BT325 cells were preloaded with 1 microM 59Fe2+ in sucrose (pH 5.8) for 60 min, and then with CP (0-300 microg/ml) for 30 min at 37 degrees C. The addition of CP, either at low (25 microg/ml) or high (300 microg/ml) concentrations, did not lead to a significant change in iron release from iron-loaded BT325 cells [22].
  • Initially and after achievement of stable euthyroidism with methimazole, plasma levels of hydrogen peroxide (H202), lipid hydroperoxides (ROOH) and ceruloplasmin (CP) and serum concentrations of thiobarbituric acid-reacting substances (TBARS) were determined [4].
  • Selective binding of LF to CP is evidenced by the results of polyacrylamide gel electrophoresis, immunodiffusion, gel filtration, and affinity chromatography [21].
  • RESULTS: A significant increase was observed in the levels of total cholesterol (TC), VLDL-C, triglycerides (TG), lipid peroxidation, ceruloplasmin (CP), glycoprotein components and glucose in the hyperlipidemic patients with/without diabetes and the increase was more pronounced (except TC) in patients with diabetes [23].

Physical interactions of CP


Regulatory relationships of CP


Other interactions of CP

  • There were no significant correlations between values of serum CRP, RAI score, or ESR with serum CP or Tf levels [32].
  • However, this hypothesis was not consistent with the increase to the similar extent for SHBG and CP, which reflect the estrogenicity/gestagenicity of the two OCs [33].
  • The results indicate the enhanced expression of EGFR and CP in thyroid carcinomas [5].
  • Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity [25].
  • Immunoreactive caeruloplasmin was measured by rate nephelometry, and ferroxidase activity determined by measuring loading of ferrous iron onto iron-free transferrin [34].

Analytical, diagnostic and therapeutic context of CP

  • Plasma MDA, CP, and erythrocyte GSH levels were significantly higher than in the control group (p<0.001, p<0.001 and p<0.01, respectively) [35].
  • We quantified concentrations of CP and TF by immunoassay in AD (n = 17) and PD (n = 12) cerebrospinal fluid (CSF) to determine whether these proteins could serve as disease markers [19].
  • EGFR and CP thus appear to be valuable tools for differential diagnosis between benign and malignant thyroid neoplasms [5].
  • We sought to identify interrelationships between the copper and iron systems by measuring copper, ceruloplasmin, ferroxidase, ferritin, transferrin, iron, and iron-binding capacity in a group of hemodialysis patients [36].
  • Furthermore, the D544E polymorphism resulted in significantly reduced serum ceruloplasmin levels and ferroxidase activity in heteroallelic patients and in expression of mainly apo-ceruloplasmin in cell culture [37].


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  2. Human ceruloplasmin. Tissue-specific expression of transcripts produced by alternative splicing. Yang, F.M., Friedrichs, W.E., Cupples, R.L., Bonifacio, M.J., Sanford, J.A., Horton, W.A., Bowman, B.H. J. Biol. Chem. (1990) [Pubmed]
  3. Ceruloplasmin immunoreactivity in neurodegenerative disorders. Loeffler, D.A., Sima, A.A., LeWitt, P.A. Free Radic. Res. (2001) [Pubmed]
  4. Oxidation products and antioxidant markers in plasma of patients with Graves' disease and toxic multinodular goiter: effect of methimazole treatment. Bednarek, J., Wysocki, H., Sowinski, J. Free Radic. Res. (2004) [Pubmed]
  5. Immunohistochemical demonstration of epidermal growth factor receptor and ceruloplasmin in thyroid diseases. Song, B. Acta Pathol. Jpn. (1991) [Pubmed]
  6. Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Loeffler, D.A., LeWitt, P.A., Juneau, P.L., Sima, A.A., Nguyen, H.U., DeMaggio, A.J., Brickman, C.M., Brewer, G.J., Dick, R.D., Troyer, M.D., Kanaley, L. Brain Res. (1996) [Pubmed]
  7. MR imaging of cerebral cortical involvement in aceruloplasminemia. Grisoli, M., Piperno, A., Chiapparini, L., Mariani, R., Savoiardo, M. AJNR. American journal of neuroradiology. (2005) [Pubmed]
  8. Role of serum ceruloplasmin and its ferroxidase activity on preterm labor. Vitoratos, N., Botsis, D., Christodoulacos, C., Contoravdis, A., Dalamaga, A., Chryssicopoulos, A. Gynecol. Obstet. Invest. (1998) [Pubmed]
  9. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Vulpe, C.D., Kuo, Y.M., Murphy, T.L., Cowley, L., Askwith, C., Libina, N., Gitschier, J., Anderson, G.J. Nat. Genet. (1999) [Pubmed]
  10. Hepatic iron overload associated with a decreased serum ceruloplasmin level in a novel clinical type of aceruloplasminemia. Kono, S., Suzuki, H., Takahashi, K., Takahashi, Y., Shirakawa, K., Murakawa, Y., Yamaguchi, S., Miyajima, H. Gastroenterology (2006) [Pubmed]
  11. Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin. Wang, T., Weinman, S.A. Gastroenterology (2004) [Pubmed]
  12. Ferritins, iron uptake and storage from the bacterioferritin viewpoint. Carrondo, M.A. EMBO J. (2003) [Pubmed]
  13. Midpregnancy serum C-peptide concentration and subsequent pregnancy-induced hypertension. Yasuhi, I., Hogan, J.W., Canick, J., Sosa, M.B., Carpenter, M.W. Diabetes Care (2001) [Pubmed]
  14. Ceruloplasmin expression and its role in iron transport in C6 cells. Chang, Y.Z., Qian, Z.M., Du, J.R., Zhu, L., Xu, Y., Li, L.Z., Wang, C.Y., Wang, Q., Ge, X.H., Ho, K.P., Niu, L., Ke, Y. Neurochem. Int. (2007) [Pubmed]
  15. Invasive neonatal candidiasis: comparison of albicans and parapsilosis infection. Faix, R.G. Pediatr. Infect. Dis. J. (1992) [Pubmed]
  16. One-step purification of recombinant human papillomavirus type 16 E7 oncoprotein and its binding to the retinoblastoma gene product. Kasher, M.S., Wakulchik, M., Cook, J.A., Smith, M.C. BioTechniques (1993) [Pubmed]
  17. mu-1,2-peroxo diferric complex formation in horse spleen ferritin. A mixed H/L-subunit heteropolymer. Zhao, G., Su, M., Chasteen, N.D. J. Mol. Biol. (2005) [Pubmed]
  18. Characterization, mapping, and expression of the human ceruloplasmin gene. Yang, F., Naylor, S.L., Lum, J.B., Cutshaw, S., McCombs, J.L., Naberhaus, K.H., McGill, J.R., Adrian, G.S., Moore, C.M., Barnett, D.R. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  19. Ceruloplasmin is increased in cerebrospinal fluid in Alzheimer's disease but not Parkinson's disease. Loeffler, D.A., DeMaggio, A.J., Juneau, P.L., Brickman, C.M., Mashour, G.A., Finkelman, J.H., Pomara, N., LeWitt, P.A. Alzheimer disease and associated disorders. (1994) [Pubmed]
  20. Effect of lactoferrin on the ferroxidase activity of ceruloplasmin. Sokolov, A.V., Pulina, M.O., Zakharova, E.T., Shavlovski, M.M., Vasilyev, V.B. Biochemistry Mosc. (2005) [Pubmed]
  21. Interaction of lactoferrin with ceruloplasmin. Zakharova, E.T., Shavlovski, M.M., Bass, M.G., Gridasova, A.A., Pulina, M.O., De Filippis, V., Beltramini, M., Di Muro, P., Salvato, B., Fontana, A., Vasilyev, V.B., Gaitskhoki, V.S. Arch. Biochem. Biophys. (2000) [Pubmed]
  22. Ceruloplasmin promotes iron uptake rather than release in BT325 cells. Qian, Z.M., Tsoi, Y.K., Ke, Y., Wong, M.S. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (2001) [Pubmed]
  23. Lipid profile, oxidant-antioxidant status and glycoprotein components in hyperlipidemic patients with/without diabetes. Kaviarasan, K., Arjunan, M.M., Pugalendi, K.V. Clin. Chim. Acta (2005) [Pubmed]
  24. Iron incorporation into apoferritin. The role of apoferritin as a ferroxidase. Bakker, G.R., Boyer, R.F. J. Biol. Chem. (1986) [Pubmed]
  25. Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity. Griffiths, T.A., Mauk, A.G., MacGillivray, R.T. Biochemistry (2005) [Pubmed]
  26. Limited protection against iron-induced lipid peroxidation by cord blood plasma. Lindeman, J.H., Houdkamp, E., Lentjes, E.G., Poorthuis, B.J., Berger, H.M. Free Radic. Res. Commun. (1992) [Pubmed]
  27. Iron-induced ascorbate oxidation in plasma as monitored by ascorbate free radical formation. No spin-trapping evidence for the hydroxyl radical in iron-overloaded plasma. Minetti, M., Forte, T., Soriani, M., Quaresima, V., Menditto, A., Ferrari, M. Biochem. J. (1992) [Pubmed]
  28. Promotion of glutathione-gamma-glutamyl transpeptidase-dependent lipid peroxidation by copper and ceruloplasmin: the requirement for iron and the effects of antioxidants and antioxidant enzymes. Glass, G.A., Stark, A.A. Environ. Mol. Mutagen. (1997) [Pubmed]
  29. The ceruloplasmin and hydrogen peroxide system induces alpha-synuclein aggregation in vitro. Kim, K.S., Choi, S.Y., Kwon, H.Y., Won, M.H., Kang, T.C., Kang, J.H. Biochimie (2002) [Pubmed]
  30. Induction of ceruloplasmin synthesis by IFN-gamma in human monocytic cells. Mazumder, B., Mukhopadhyay, C.K., Prok, A., Cathcart, M.K., Fox, P.L. J. Immunol. (1997) [Pubmed]
  31. Human mitochondrial ferritin expressed in HeLa cells incorporates iron and affects cellular iron metabolism. Corsi, B., Cozzi, A., Arosio, P., Drysdale, J., Santambrogio, P., Campanella, A., Biasiotto, G., Albertini, A., Levi, S. J. Biol. Chem. (2002) [Pubmed]
  32. Levels of antioxidant proteins and soluble intercellular adhesion molecule-1 in serum of patients with rheumatoid arthritis. Cogalgil, S., Taysi, S. Ann. Clin. Lab. Sci. (2002) [Pubmed]
  33. Effects of desogestrel and gestodene in low-dose oral contraceptive combinations on lipid and lipoprotein status. A randomized prospective study. Granata, A., Sobbrio, G.A., D'Arrigo, F., Barillari, M., Curasì, M.P., Egitto, M., Trimarchi, F., Granese, D., Pullè, C. Acta Eur. Fertil. (1990) [Pubmed]
  34. The ferroxidase activity of caeruloplasmin is reduced in haemodialysis patients. Roxborough, H.E., Mercer, C., McMaster, D., Maxwell, A.P., Young, I.S. Nephron (2000) [Pubmed]
  35. Carnitine and antioxidants levels in patients with rheumatoid arthritis. Kiziltunc, A., Coğalgil, S., Cerrahoğlu, L. Scand. J. Rheumatol. (1998) [Pubmed]
  36. Relationships between the copper and iron systems in hemodialysis patients and variables affecting these systems. Kirschbaum, B. Biological trace element research. (2000) [Pubmed]
  37. Functional relevance of ceruloplasmin mutations in Parkinson's disease. Hochstrasser, H., Tomiuk, J., Walter, U., Behnke, S., Spiegel, J., Krüger, R., Becker, G., Riess, O., Berg, D. FASEB J. (2005) [Pubmed]
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