Ceruloplasmin synthesis

The copper transport function of ceruloplasmin has been documented in several reviews (e.g. see refs. 15, 42, 43) and a transport function established. The turnover of ceruloplasmin allows copper ions to move from the major sites of ceruloplasmin synthesis in liver cells [44,45] to peripheral tissues for incorporation into copper-dependent enzymes [46,47], but transport mechanisms may also be active which involve copper atoms in the intact protein. However, the complexity of the protein has made it difficult to determine which, if any, of the six integral copper atoms are involved in copper delivery or whether there exist additional... 

Sugawara N, Sugawara C. 1984. Effect of silver on ceruloplasmin synthesis in relation to low-molecular-weight protein. Toxicology Letters 20 99-104. 

Evidence for Ceruloplasmin Synthesis from Cu64 by Isolated Liver. Figure 8 shows the linear disappearance of Cu64 activity from the perfusion blood during the first 4 hours of a 5-hour perfusion. Analyses of small lobes of the liver removed at 5 minutes, 3 hours, and 5 hours revealed that at least 53% of the initial Cu64 activity was retained by the liver and more than 10% was in the bile collected during the perfusion. Preferential concentration of parenterally administered Cu64 in the liver of intact animals has been described (16). 

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. 

The reduction in the serum value of ceruloplasmin led to the assumption that a primary synthesis disturbance was of particular pathogenic importance. There are several observations which contradict this hypothesis, suggesting that the disturbance in ceruloplasmin synthesis is probably a secondary consequence of the underlying metabolic defect. The introduction of copper into ceruloplasmin is possibly inhibited as a result of a dysfunctional apoprotein of ceruloplasmin. 

During the first few days after birth, serum copper concentration in the baby rises from 50-150 /xg/100 mL, presumably because of increases in ceruloplasmin synthesis, and then it subsides again to normal level of 100 /xg/100 mL and is maintained throughout life (119), Thus, an infant needs at least 14 /xg Cu/kg to maintain his copper balance while in children, 60-100 /xg Cu/kg would be the minimal requirement. It also can be seen that low intake of copper by the mother during gestation can diminish copper stores in the embryo and thus can contribute to newborn copper deficiency. 

Since about 90% of plasma copper is bound to ceruloplasmin, factors that increase the hepatic synthesis of ceruloplasmin, such as an APR or the oral contraceptive pill, will increase plasma copper independently of dietary copper intake. In premature infants with fiver immaturity and low ceruloplasmin synthesis, plasma copper values below 30 IXg/L (<5pmol Cu per L) suggest the necessity for increased copper input. 

It has been reported that ceruloplasmin increases iron uptake into cultured human cells (Mukhopadhyay et al, 1998), although this apparently contradictory in vitro observation must be set against the in vivo evidence presented above from both animal and human studies. Plasma ceruloplasmin levels increase markedly in anaemia, consistent with a physiological role in tissue iron mobilization, and this effect is due to transcriptional activation of ceruloplasmin mRNA synthesis (Mukhopadhyay et al, 2000). 

The disease results from mutations within the ATP7B gene on the short arm of chromosome 13 [23, 24]. This gene encodes a protein which appears to be involved in copper transport coupled with the synthesis of ceruloplasmin and other cuproproteins. 

The acute-phase response is characterised by the enhanced (two- to threefold) synthesis of a number of proteins, such as antiproteinases, complement components, fibrinogen and ceruloplasmin, which are normally synthesised at fairly low rates. The rate of synthesis of some proteins is enhanced 100-1000-fold - for example, C-reactive protein, a-macroglobulin and acid-1-glycoprotein. Thus, serum levels of these proteins serve as indicators of disease. 

The precise function of many acute-phase proteins is not known. C-reactive protein binds lipids, whilst a-macroglobulin and ceruloplasmin can scavenge some reactive oxygen metabolites. However, many acute-phase proteins are glycoproteins and can bind to bacterial surfaces hence, they may serve as non-specific opsonins for phagocytosis, and their synthesis is stimulated by IL-1 and IL-6. 

In plasma, ca 90 vvl or copper is in the ineialloprotein ceruloplasmin. also known as ay-globulin, mol wi 151.000. which contains 8 atoms of copper per molecule. Ceruloplasmin has been identified as a ferroxi dasctll which catalyses Ihc oxidation of aromatic amines and of Pc to Fe . The ferric ion is then incorporated inlo iranslcrrin which is necessary lor the transport ol iron to tissues involved in Ihe synthesis or iron-containing compounds, e.g.. hemoglobin. Lowered levels of ceruloplasmin interfere with hemoglobin synthesis. 

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... 

Biological Roles of Zinc and Copper. Zinc and copper are essential cofactors at the active site of a number of enzymes. Zinc is a component of more than 200 proteins and enzymes (Table II). Copper, sim-lleT to iron, participates both in redox reactions and as a proton doner (Table III). The normal human adult body contains approximately 50-100 mg of copper and 2.0 g of zinc. The vast majority of tissue copper is found in the liver, kidney, heart and brain. In the blood, copper exists within the red blood cell as superoxide dlsmutase and in the serum as ceruloplasmin. Copper is a component of aerobic metabolism, bone synthesis, and erythrocyte development. Zinc is found primarily in the liver, kidney, bone and prostate. Zinc is essential for normal growth of tissues, wound repair, skin structure, reproduction, taste perception, and the prevention of dwarfism. 

High levels of zinc stimulate the synthesis of metallothionein in the small intestines. The elevated levels of metallothionein then serve as a depot for the binding of high levels of zinc consumed in subsequent meals. The induced protein has been shown to limit the amount of zinc entering the bloodstream with consumption of a high-zinc diet (Menard ef o/., 1981). High doses of copper can induce metallothionein synthesis to the same extent as can zinc. At levels near those found in the diet, zinc is a potent inducer while copper is only a weak inducer. Normally, hepatic metaiiothionein contains mainly zinc, whereas kidney metallothionein contains copper and, when present in the diet, cadmium. The copper entering the liver may be stored in hepatic metallothionein and released into the plasma in ceruloplasmin or secreted in the bile later. 

Experimentally induced copper deficiency produces anemia in a variety of animals. It produces an anemia. As one might expect, this type of anemia cannot be cured by iron. The heart may enlarge and the mitochondria of the heart may enlarge dramatically. The heart and arteries may rupture with deficiency, probably because of a drop in the activity of lysyl oxidase, a copper melallt enzyme involved in the synthesis of connective tissue proteins. Skeletal defects, such as osteoporosis, occur in experimental copper deficiency. Infections appear to affect copper metabolism. Infections can induce a threefold increase in plasma ceruloplasmin levels. Copper-deficient animals have a reduced ability to exercise, as measured by running on treadmills (Klevay and Medeiros, 1996). 

It has been known for some time that copper deficiency leads to anemia and failure of the erythropoietic system to matiure (50,51). Although the exact mechanism involved is still not well defined, recent evidence suggests that copper may be essential for iron absorption and mobilization for hemoglobin synthesis. A ferrous-to-ferric cycle with respect to the role of copper in iron metabolism has been proposed by several workers. Role of ceruloplasmin in the spontaneous oxidation of... 

The chemical nature of the hormone seems to have varying effect on copper metabolism. Gonadal hormones, for example, increase ceruloplasmin by a mechanism of de novo synthesis of the protein independent of copper concentration in the liver, whereas hormones of the thyroid, adrenal, and pituitary influence copper metabolism in an indirect manner by decreasing its biliary excretion 144),... 

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