Wilson Ceruloplasmin

Ceruloplasmin Binds Copper, Low Levels of This Plasma Protein Are Associated With Wilson Disease... 

Ceruloplasmin contains substantial amounts of copper, but albumin appears to be more important with regard to its transport. Both Wilson disease and Menkes disease, which reflect abnormahties of copper metabohsm, have been found to be due to mutations in genes encoding copper-binding P-type ATPases. 

Copper appears as the a2-globulin ceruloplasmin in the human body (Sarkar 1994). Deficiency of this protein in serum is characteristic of both Menkes and Wilson s diseases. Wilson s disease is an abnormal storage of Cu(II) in body tissues. Cu(II) in biological material can be determined by spectrophotometry or by FAAS, ceruloplasmin in serum by a spectrophotometric method. 

Figure 12.4 Proposed path for the intracellular transfer of Cu(I) by Atxl. Copper destined for incorporation into the vascular multicopper oxidase Fet3 requires both Ctrl and Ccc2. Cytoplasmic Cu(I)-Atxl, but not apo-Atxl, associates with the amino-terminal domain of Ccc2 and Cu(I) is transferred to the latter. (Inset) A proposed mechanism for the exchange of Cu(I) involving two- and three-coordinate Cu-bridged intermediates. The human homologues of Atxl (Hahl), Ccc2 (Menkes and Wilson s proteins) and Fet3 (ceruloplasmin) are likely to employ similar mechanisms. Reprinted with permission from Pufahl et al., 1997. Copyright (1997) American Association for the Advancement of Science.

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

Figure 18.4 Proteins involved in copper uptake, incorporation into ceruloplasmin and biliary excretion in normal and Wilson s disease hepatocytes. (From Crichton and Ward, 2006. Reproduced with permission from John Wiley Sons., Inc.)...

Optional studies HIV antibody screen Chest x-ray Urine drug screen Ceruloplasmin (if Wilson s disease suspected) Lumbar puncture (spinal tap) Electroencephalograph (EEG)... 

Recent publications signal the continued interest in the function of this protein. It has been called a stress enzyme, involved in influenza virus infection (Tomas and Toparceanu, 1986). An explanation for Wilson s disease in terms of a genetic defect resulting in failure to convert from a neonatal (i.e., low) level of ceruloplasmin and copper to a normal adult level has been reported (Srai et al., 1986). Tissue specificity for the binding of ceruloplasmin to membranes was demonstrated in a study investigating the possible role of ceruloplasmin-specific receptors in the transfer of copper from ceruloplasmin to other copper-containing proteins (Orena et al, 1986). Ceruloplasmin has been shown to be effective in transferring copper to Cu,Zn-SOD in culture (Dameron and Harris, 1987), as has copper albumin. In view of the variable content of copper in this protein, it is not clear which copper is transferred. 

As demonstrated with "Cu in rats, (Cu,Zn)-SOD receives its copper from ceruloplasmin after 2-3 days The (Cu,Zn)-SOD activity in erythrocytes is reduced in Cu deficiency, as shown with several species With rats e.g. during Cu depletion, plasma Cu and ceruloplasmin were decreased by 78 and 75% respectively against 72 % and only 56 % for the blood cell Cu and (Cu,Zn)-SOD respectively In three patients with Wilson s disease the SOD level of erythrocytes was normal, although the disease is characterized by an accumulation of Cu in the liver e.g. and usually by low concentrations and sometimes the absence of ceruloplasmin... 

Copper 80 mg 2-3 mg Metal storage/transport (ceruloplasmin) enzymes in synthesis of cartilage, bone, myelin interaction with iron Occurs in malnutrition, TPN anemia, neutropenia, skeletal and neurological defects Danger in Wilson s disease... 

Scheinberg, I. H., and Gitlin, D., Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson s disease). Science 116, 484-485 (1952). 

Wilson s disease is a pathological accumulation of copper in tissue which is later released into the bloodstream, leading to anaemia, and final accumulation of copper in liver and brain. It is the result of a mutation in the Wilson s disease gene in chromosome 13 which ordinarily codes for a cation transporting ATPase so that copper can be incorporated into ceruloplasmin prior to excretion. Also known as ferroxi-dase, in acknowledgement of its primary function as an oxidoreductase responsible for electron transfer, this enzyme contains iron and, more importantly, six copper atoms. It accounts for the transport of 90% of copper in the plasma so any impairment in its production or efficacy has a major impact on copper homeostasis. The greatly reduced concentration of ceruloplasmin in the blood of Wilson s disease sufferers correlates with their inability to metabolize copper effectively. It leads to chronic liver disease, for which the only real cure is a liver transplant,... 

A word of comment on the high Cu64 content of the bile seems justifiable, since the exact chemical form of copper excreted in the bile has not been determined. The possibility that ceruloplasmin or some copper-containing metabolite of ceruloplasmin is normally excreted in the bile has not been carefully examined. The abnormal elevation of the serum ceruloplasmin level in acute biliary obstruction (7), and the abnormally low serum ceruloplasmin seen in some cases of advanced liver disease, particularly Wilson s disease (2, 3), are in keeping with the liver being the site of ceruloplasmin synthesis and excretion. 

Wilson s disease is a copper storage disorder that is apparently due to an inherited lesion in the copper excretion mechanism. One in 200-400 persons is a carrier of the disease. Diagnosis may be made by measuring serum ceruloplasmin levels. Whereas normal serum ceruloplasmin is 200-400 mg/L, in Wilson s disease patients it is well below 200 mg/L. Liver copper in these patients (determined by biopsy) is more than 250 /xg/g, whereas normal individuals show a value of only 20-45 /xg/g. Liver function deterioration is the most prominent symptom of Wilson s disease. Treatment includes chelation therapy with penicillamine. 

Wilson s disease Autosommal recessive, low serum ceruloplasmin and increased hepatic copper content. 

Other types of protein in the blood can identify specific liver diseases, for example ceruloplasmin is reduced in Wilson s disease, lack of 1-antitrypsin is an uncommon cause of cirrhosis and high levels of ferritin is a marker of haemochromatosis. 

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