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PubMed1993

Ceruloplasmin and copper transport during the latter part of gestation in the rat.

We have examined the tissue uptake of 67Cu from ceruloplasmin versus albumin and transcuprein, after its intravenous administration to pregnant rats, in the last 4 days of gestation. 67Cu infused as in vivo-labeled ceruloplasmin remained on ceruloplasmin in the maternal circulation over the 4- to 6-hr time period examined, as determined by gel chromatography and immunoreactivity. That infused as in vitro-labeled serum was initially on transcuprein and albumin but soon also with new ceruloplasmin. On the basis of percent dose as well as total actual Cu transferred (taking into account the sizes of the two plasma Cu pools), ceruloplasmin was the preferred source of Cu for most tissues. Total uptake of Cu from ceruloplasmin was seven times greater than that from albumin and transcuprein for the placenta, whole fetus, and fetal liver. It was 2- to 6-fold greater for other tissues (except liver and kidney). When synthesis of maternal 67Cu-ceruloplasmin (from 67Cu administered on albumin and transcuprein) was inhibited with cycloheximide, uptake by nonhepatic tissues was reduced markedly. In the fetal circulation, entering 67Cu was initially associated with transcuprein and alpha-fetoprotein (or albumin), but then also appeared with ceruloplasmin. Specific receptors for ceruloplasmin were detected on membranes from the placenta as well as fetal liver; mRNA for ceruloplasmin was detected on the endoplasmic reticulum-bound polyribosomes of placenta/yolk sac, and of fetal and maternal liver. We conclude that Cu destined for the fetus is delivered mainly or exclusively by ceruloplasmin. It may enter via placental receptors, arriving in fetal plasma in ionic form, for later incorporation into fetal ceruloplasmin. The importance of ceruloplasmin as a source of plasma Cu for nonhepatic organs is also confirmed.

Animals↗

PubMed1995

Ceruloplasmin: an endogenous depolarizing factor in neurons?

The biological effects of ceruloplasmin have been exclusively ascribed to its roles as a copper carrier and an antioxidant. Although neuronal involvement of ceruloplasmin is closely related to aging and certain neuronal disorders, neuronal effects of ceruloplasmin are unknown and the possible modulation of membrane potential and ion channels by ceruloplasmin has not been investigated. In the present study, the membrane electrical properties of neuroblastoma cells in the presence of ceruloplasmin were studied using the patch-clamp technique. Ceruloplasmin induced a rapid and sustained membrane depolarization. This capacity of ceruloplasmin was abolished either when the copper was removed from ceruloplasmin or when ceruloplasmin was heat-inactivated. The depolarizing effect of ceruloplasmin was not due to an enhanced Ca2+ or Na+ influx but it seemed to result from a reduced K+ efflux since ceruloplasmin significantly inhibited a TEA-sensitive delayed rectifier K+ channel. To our knowledge, this is the first report which indicates that ceruloplasmin is an endogenous neuronal depolarizing factor.

Calcium↗

PubMed1991

Tissue-specific ceruloplasmin gene expression in the mammary gland.

Using a ceruloplasmin cDNA clone in RNA blot analysis, a single 3.7 kb ceruloplasmin-specific transcript was detected in rat mammary gland tissue from pregnant and lactating animals. Ceruloplasmin gene expression in the mammary gland was tissue-specific, with no evidence of expression in brain, heart or other extrahepatic tissues. Ceruloplasmin mRNA was also detected in mammary gland tissue from male, virgin female and non-pregnant/multiparous animals, and the abundance of ceruloplasmin-specific transcripts in virgin female rats was independent of their stage of oestrus. In virgin female mammary gland the content of ceruloplasmin mRNA was 20% of that in hepatic tissue from these animals and approx. 2-3-fold greater than that found in mammary gland tissue of pregnant or lactating animals. Development studies revealed ceruloplasmin gene expression in male and female mammary gland by only 2 weeks of age, prior to the onset of puberty. Biosynthetic studies indicated that the ceruloplasmin mRNA in mammary gland tissue was translated into a 132 kDa protein qualitatively similar to that synthesized in liver. By in situ hybridization, ceruloplasmin gene expression was localized to the epithelium lining the mammary gland alveolar ducts, without evidence of expression in the surrounding mesenchyme. Ceruloplasmin gene expression was also detected in a human breast adenocarcinoma cell line and in biopsy tissue from women with invasive ductal carcinoma. Taken together, these data indicate that the mammary gland is a prominent site of extrahepatic ceruloplasmin gene expression and add to the evidence that ceruloplasmin biosynthesis is associated with growth and differentiation in non-hepatic tissues.

Aging↗

PubMed2005

Functional relevance of ceruloplasmin mutations in Parkinson's disease.

Increased iron levels of the substantia nigra and the discovery of ceruloplasmin mutations in patients with Parkinson's disease (PD) imply impaired iron metabolism in this neurodegenerative disorder. Ceruloplasmin has ferroxidase activity oxidizing iron(II) to iron(III). In the present study, we analyzed the amount of ceruloplasmin, iron, ferritin, and transferrin and the ceruloplasmin ferroxidase activity in serum of patients with the diagnosis of PD carrying the ceruloplasmin mutations I63T, D544E, and R793H. The impact of these missense mutations on the biosynthesis of holo-ceruloplasmin was investigated in cell culture experiments. Functional relevance was found for the ceruloplasmin mutations I63T and D544E. In vivo, the I63T mutation resulted in half the normal ceruloplasmin concentration and markedly reduced ferroxidase activity in serum from a heteroallelic PD patient. In cell culture, the I63T glycosylphosphatidylinositol (GPI)-linked ceruloplasmin isoform was retained in the endoplasmatic reticulum of human embryonic kidney cells. 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. Our studies indicate that altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in PD.

Alleles↗

PubMed1995

Antiarrhythmic effects of ceruloplasmin during reperfusion in the ischemic isolated rat heart.

The ability of ceruloplasmin, an important serum antioxidant, to reduce the vulnerability of the isolated rat heart to reperfusion arrhythmias has been investigated. Bovine plasma ceruloplasmin was purified by chromatography on aminoethyl-agarose. Isolated rat hearts were submitted to 15 min of regional ischemia and 10 min of reperfusion. The dose-effect relationship and the role of ceruloplasmin conformational integrity in cardioprotection were established by treatment of ischemic hearts with ceruloplasmin at various concentrations (0.25, 0.5, 1, and 2 microM) and at different degrees of conformational integrity (A610/A280 = 0.02, 0.04, and 0.06), 5 min before reperfusion. Deferoxamine (20-500 microM) was used as a positive control. As negative controls we used chemically inactivated ceruloplasmin (1 microM), heat-denatured ceruloplasmin (1 microM), and albumin (1-4 microM). In the control group during the first 5 min of reperfusion, the incidence of total ventricular fibrillation was 100% and of irreversible ventricular fibrillation was 83%. The incidence of reversible and irreversible ventricular fibrillation was significantly decreased in the ceruloplasmin-treated groups in both a dose and molecular integrity dependent manner. Ceruloplasmin had no effect on the incidence of ventricular tachycardia. Deferoxamine reduced the incidence of ventricular fibrillation to the same degree as ceruloplasmin but at concentrations much higher than those of ceruloplasmin. Chemically inactivated ceruloplasmin, heat-denatured ceruloplasmin, and albumin had no protective effects on reperfusion-induced arrhythmias.

Animals↗

PubMed1994

Intact human ceruloplasmin oxidatively modifies low density lipoprotein.

Ceruloplasmin is a plasma protein that carries most of the copper found in the blood. Although its elevation after inflammation and trauma has led to its classification as an acute phase protein, its physiological role is uncertain. A frequently reported activity of ceruloplasmin is its ability to suppress oxidation of lipids. In light of the intense recent interest in the oxidation of plasma LDL, we investigated the effects of ceruloplasmin on the oxidation of this lipoprotein. In contrast to our expectations, highly purified, undegraded human ceruloplasmin enhanced rather than suppressed copper ion-mediated oxidation of LDL. Ceruloplasmin increased the oxidative modification of LDL as measured by thiobarbituric acid-reacting substances by at least 25-fold in 20 h, and increased electrophoretic mobility, conjugated dienes, and total lipid peroxides. In contrast, ceruloplasmin that was degraded to a complex containing 115- and 19-kD fragments inhibited cupric ion oxidation of LDL, as did commercial preparations, which were also degraded. However, the antioxidant capability of degraded ceruloplasmin in this system was similar to that of other proteins, including albumin. The copper in ceruloplasmin responsible for oxidant activity was not removed by ultrafiltration, indicating a tight association. Treatment of ceruloplasmin with Chelex-100 removed one of seven copper atoms per molecule and completely blocked oxidant activity. Restoration of the copper to ceruloplasmin also restored oxidant activity. These data indicate that ceruloplasmin, depending on the integrity of its structure and its bound copper, can exert a potent oxidant rather than antioxidant action on LDL. Our results invite speculation that ceruloplasmin may be in part responsible for oxidation of LDL in blood or in the arterial wall and may thus have a physiological role that is quite distinct from what is commonly believed.

Ceruloplasmin↗

PubMed2003

Astrocytic ceruloplasmin expression, which is induced by IL-1beta and by traumatic brain injury, increases in the absence of the IL-1 type 1 receptor.

IL-1alpha and IL-1beta are induced immediately after insults to the brain, and signaling through the type 1 IL-1 receptor is essential for a normal microglial and astroglial response to injury. To better understand which genes are induced in astrocytes by IL-1beta, we used the unbiased technique of differential display to analyze mouse astroglial gene expression after IL-1beta treatment. Two novel genes were induced, as well as the gene for ceruloplasmin, a ferroxidase with antioxidant properties. Ceruloplasmin was analyzed further by Northern and Western blot. RNA and protein levels of ceruloplasmin were increased when astrocytes were treated with IL-1beta. To determine whether the IL-1 type 1 receptor (IL-1R1) is essential for the injury-induced expression of ceruloplasmin, a Western blot analysis was performed after a traumatic brain injury on mice that were IL-1R1-deficient. Ceruloplasmin increased significantly above controls after injury; however, injury-induced levels of ceruloplasmin were lower in IL-1R1-deficient (2.7-fold increase) than in the wild-type animals (3.5-fold increase). These data indicate that while IL-1R1 deletion has a slight effect on ceruloplasmin expression, it is not essential for either the basal or the induced expression of ceruloplasmin in vivo. Since ceruloplasmin buffers free copper, oxidizes ferrous iron, and catalyzes the dismutation of free radicals, increased levels of ceruloplasmin likely protect neurons and glia from sustaining damage after injury. Furthermore, as the IL-1R1 has been proposed to be a target for achieving neuroprotection after injury, these data suggest that the protection afforded by ceruloplasmin will be retained even when the IL-1R1 is antagonized.

Animals↗

PubMed1993

Synthesis and turnover of ceruloplasmin in rats treated with 17 beta-estradiol.

The effects of estrogen on synthesis and turnover of ceruloplasmin were studied in adult female Fischer rats. Daily treatment with 140 microgram 17 beta-estradiol resulted in a slow rise of ceruloplasmin concentrations, as measured by p-phenylenediamine oxidase activity, leading to a 70% increase by 7 days and a tripling by Day 14. Ceruloplasmin protein concentrations increased to the same degree, based on yields of the protein obtained during purification. Effects of estrogen on rates of synthesis (incorporation of [3H]leucine) were followed, using immunoprecipitation of total ceruloplasmin or isolation of its two major isoforms (Rfs 0.4 and 0.6 in native gel electrophoresis). Synthesis was increased by 7 days and was 2.5 times that of controls by Day 14. Both forms of ceruloplasmin showed the same specific activities and degree of increase in rate of synthesis. Rates of ceruloplasmin turnover were unaffected, based on double labeling with 3H- and 14C-leucine, but were three- to fourfold faster than for total plasma protein. The enzymatically more active 0.6 Rf form of ceruloplasmin had a faster turnover rate than the 0.4 Rf form. Estrogen treatment doubled ceruloplasmin mRNA levels by 7 days and almost tripled them by Day 14. Most of the ceruloplasmin mRNA was associated with the endoplasmic reticulum-bound polyribosomes. We conclude that estrogen increases the rate of synthesis of two forms of ceruloplasmin by indirectly increasing liver concentrations of its mRNA but has no effect on ceruloplasmin turnover.

Animals↗

PubMed2006

Up-regulation of brain ceruloplasmin in thrombin preconditioning.

Pretreatment with low-dose thrombin attenuates brain edema induced by iron or intracerebral hemorrhage (ICH). Ceruloplasmin is involved in iron metabolism by oxidizing ferrous iron to ferric iron. The present study examines whether thrombin modulates brain ceruloplasmin levels and whether exogenous ceruloplasmin reduces brain edema induced by ferrous iron in vivo. In the first set of experiments, rats received intracerebral infusion of saline or 1 U thrombin into the right basal ganglia. Rats were killed 1, 3, or 7 days later for Western blot analysis and RT-PCR analysis. In the second set of experiments, rats received either ferric iron, ferrous iron, or ferrous iron plus ceruloplasmin, then were killed 24 hours later for brain edema measurement. We found that ceruloplasmin protein levels in the ipsilateral basal ganglia increased on the first day after thrombin stimulation and peaked at day 3. Brain ceruloplasmin levels were higher after thrombin infusion than after saline injection. RT-PCR showed that brain ceruloplasmin mRNA levels were also up-regulated after thrombin injection (p < 0.05). We also found ipsilateral brain edema after intracerebral infusion of ferrous iron but not ferric iron at 24 hours. Co-injection of ferrous iron with ceruloplasmin reduced ferrous iron-induced brain edema (p < 0.05). Our results demonstrate that thrombin increases brain ceruloplasmin levels and exogenous ceruloplasmin reduces ferrous iron-induced brain edema, suggesting that ceruloplasmin up-regulation may contribute to thrombin-induced brain tolerance to ICH by limiting the injury caused by ferrous iron released from the hematoma.

Animals↗

PubMed1981

Circulating ceruloplasmin is an important source of copper for normal and malignant animal cells.

The relative uptake of copper from ceruloplasmin and non-ceruloplasmin plasma pools, by normal and malignant cells, was investigated in vivo and in vitro, using 64Cu and 67Cu. 1. Most of the copper administered intravenously to normal and tumor-bearing rats was removed within 1 h, a substantial portion entering the liver. There were differences in the apparent avidity of individual tissue for ceruloplasmin vs. ionic copper, but when calculated on the basis of actual microgram absorbed, all showed a preference for ceruloplasmin. 2. Appreciable amount of copper from either source were also absorbed by the tumors, and cultured Ehrlich ascites tumor cells showed a rapid uptake and marked preference for ceruloplasmin over non-ceruloplasmin copper, as did primary rat muscle cell cultures. 3. Ceruloplasmin protein was also absorbed by normal and neoplastic rat tissues, but less rapidly than ceruloplasmin copper, as determined by administration of pure [3H]leucine- or [125I]ceruloplasmin. Copper deficiency did not accelerate this process. 4. It is concluded that, at least in rat, ceruloplasmin is the preferred plasma source of copper for normal and malignant cells, and that the copper on ceruloplasmin turns over more rapidly than the protein moiety, a finding consistent with its role as a copper transport protein.

Animals↗

PubMed1993

Ceruloplasmin inhibits carbonyl formation in endogenous cell proteins.

Exposure of cells to oxygen radicals results in cellular injury and protein oxidation. Ceruloplasmin is a plasma antioxidant that increases in concentration during inflammation. Therefore, the ability of ceruloplasmin to protect endothelial cells from neutrophil-mediated injury was investigated. The inhibition of protein oxidation by ceruloplasmin was also examined in neutrophil and endothelial cell proteins by analysis of carbonyl formation. In addition, the iron oxidation state was measured to determine the effect of ceruloplasmin ferroxidase activity in oxygen-radical generating systems. Ceruloplasmin significantly (p < .01) inhibited neutrophil-mediated cytotoxicity of endothelial cells by 48%. Carbonyl formation in phorbol myristate acetate (PMA)-stimulated neutrophil proteins was also significantly (p < .01) reduced by ceruloplasmin from 0.172 +/- 0.028 to 0.086 +/- 0.004 mole carbonyl/mole protein. Even though ceruloplasmin itself had a threefold increase in carbonyl formation (0.452 +/- 0.010 vs. 0.146 +/- 0.018 mole carbonyl/mole protein) in the presence of PMA-stimulated compared with unstimulated neutrophils, no loss of functional activity was detected. In xanthine oxidase-treated endothelial cells, ceruloplasmin significantly (p < .05) reduced carbonyl formation from 0.132 +/- 0.010 to 0.097 +/- 0.009 mole carbonyl/mole protein. Ceruloplasmin also significantly (p < .01) oxidized iron when added to PMA-activated neutrophils, thereby decreasing Fe(II) from 98 +/- 8 to 7 +/- 2 microM. Similarly, ceruloplasmin added to xanthine oxidase/hypoxanthine reactions resulted in significant (p < .01) iron oxidation, decreasing Fe(II) from 99 +/- 1 to 15 +/- 3 microM. The ability of ceruloplasmin to protect both endothelial cells and endogenous neutrophil and endothelial cell proteins from oxidative injury suggests that it may be important in regulating cellular and protein damage by oxygen radicals during inflammation.

Animals↗

PubMed2004

Value of an enzymatic assay for the determination of serum ceruloplasmin.

The serum concentration of the copper protein ceruloplasmin has been an important diagnostic indicator of Wilson's disease (WD). It is widely quoted that 95% of people with WD have low serum ceruloplasmin concentrations. Current evidence suggests that a normal serum ceruloplasmin concentration is more common in patients with WD, particularly those with liver disease, perhaps in part because of the routine use of an immunologic assay. This assay might indicate a normal level of ceruloplasmin when the enzymatic activity is lower. Enzymatic activity is the biologically relevant parameter. We compared the immunologic measurement with the enzymatic assessment of oxidase activity in patients with liver or neurologic symptoms of unknown origin in whom WD was considered in the differential diagnosis. Although a strong correlation of ceruloplasmin protein concentration with oxidase activity was observed in controls, this was not the case for these patients. Twelve patients, presenting with various types of hepatic disease, demonstrated a weak correlation between ceruloplasmin protein concentration and oxidase activity. Ten percent of patients with neurologic symptoms ( n = 41) had low ceruloplasmin concentrations and oxidase activity, and another 8% had normal ceruloplasmin concentrations associated with low oxidase activity. Although the enzymatic method is preferred for its biologic relevance, ceruloplasmin analysis is not a reliable diagnostic parameter for the diagnosis of WD in patients with liver disease. An important use of the ceruloplasmin oxidase assay is in the follow-up of patients with WD. Ceruloplasmin oxidase activity was undetectable in sera from patients with WD who were undergoing long-term chelation therapy, suggesting an early sign of copper depletion and a need for subsequent monitoring for symptoms of copper deficiency.

Ceruloplasmin↗

PubMed1967

Measurement of gastrointestinal protein loss using ceruloplasmin labeled with copper.

Ceruloplasmin labeled with (67)copper and administered intravenously to dogs, control human subjects, and patients with excessive gastrointestinal loss was shown to fulfill the requirements for a label for quantification of gastrointestinal protein loss. The radiocopper moiety was poorly absorbed from the gastrointestinal tract, not actively secreted into the intestinal tract, and did not alter significantly the metabolism of ceruloplasmin. Approximately 70% of the body pool of ceruloplasmin in both dog and man was within the intravascular space. In control human subjects the mean ceruloplasmin concentration was 30 mg per 100 ml with total circulating and total body ceruloplasmin pools of 15.5 and 22 mg per kg, respectively. In patients with excessive gastrointestinal protein loss secondary to intestinal lymphangiectasia, the serum ceruloplasmin concentration was reduced to 16 mg per 100 ml with a comparable reduction in the total circulating and total body ceruloplasmin pools to 8.8 and 12 mg per kg. The survival half-time of ceruloplasmin was 6.1 days in normal human subjects and 4.5 days in normal dogs. From 1.0 to 1.9% of the intravascular pool of ceruloplasmin was lost into the gastrointestinal tract of the dog per day, representing less than 11% of the over-all metabolism of this protein. In control human subjects from 1.9 to 3.9% of the intravascular pool was lost into the gastrointestinal tract each day, representing a maximum of from 11 to 22% of the over-all metabolism of this molecule. In contrast, patients with intestinal lymphangiectasia had a markedly shortened ceruloplasmin survival of 3.1 days, with from 15 to 40% of the intravascular pool of ceruloplasmin cleared into the gastrointestinal tract daily. This represented 76% of the over-all metabolism of this protein. Thus, although bulk loss of serum proteins into the gastrointestinal tract does not normally appear to be a significant factor in protein metabolism in normal dogs and men, such loss is a major factor in the pathogenesis of the hypoceruloplasminemia noted in patients with intestinal lymphangiectasia.

Animals↗

PubMed1989

Ceruloplasmin reduces the adhesion and scavenges superoxide during the interaction of activated polymorphonuclear leukocytes with endothelial cells.

The plasma protein, ceruloplasmin, has been implicated as an anti-inflammatory agent, although this property has not been demonstrated unequivocally in vivo. The role of this protein in an in vitro system of cultured endothelial cells and polymorphonuclear leukocytes (PMNs) was investigated. One of the initial steps in an inflammatory response is increased adhesion between PMNs and the endothelial lining of the blood vessels. The results showed that ceruloplasmin interferes with this process and reduces the number of phorbol myristate acetate-activated leukocytes that adhere to endothelium. Preincubation of either the activated PMNs or the endothelium with ceruloplasmin did not produce the same results, suggesting that the continuous presence of ceruloplasmin is required. During attachment PMNs become activated and release a variety of substances, including toxic oxygen species such as superoxide and hydrogen peroxide. In the in vitro system used in this study no injury occurred to the endothelial cells, as measured by 51Cr release, when activated PMNs were added with ceruloplasmin. The data show that ceruloplasmin reduced, in a dose dependent manner, the levels of superoxide produced by the activated PMNs, further supporting ceruloplasmin's previously reported role as a scavenger of superoxide. Ceruloplasmin also reduced the levels of superoxide when activated PMNs were in contact with endothelial cells. Although ceruloplasmin interfered with the copper-dependent scavenger enzyme, superoxide dismutase (SOD), in a cell-free system, ceruloplasmin had no effect on SOD in intact endothelial cells. These results suggest that ceruloplasmin may act as an anti-inflammatory agent by reducing the number of PMNs attaching to endothelium and by acting as an extracellular scavenger of superoxide.

Animals↗

PubMed1988

Transcriptional regulation of ceruloplasmin gene expression during inflammation.

Mixed sequence oligonucleotides were used to isolate a series of acute-phase human liver cDNA clones corresponding to the serum alpha 2-globulin ceruloplasmin. These clones were characterized, sequenced, and used to analyze changes in hepatic ceruloplasmin mRNA content during inflammation. In all species examined, hepatic ceruloplasmin mRNA content increased approximately 6-10-fold over control values within 24 h following the induction of inflammation. The mechanisms leading to this increase in hepatic ceruloplasmin mRNA content were studied following turpentine-induced inflammation in Syrian hamsters. Nuclear run-on assays demonstrated an increase in the relative rate of transcription of the ceruloplasmin gene within 3 h following induction, reaching maximum values by 18 h. Hepatic ceruloplasmin mRNA content increased 2-fold within 12 h following induction, reached maximum values by 24 h, and returned to control within 72 h. In contrast, serum ceruloplasmin concentration did not increase until 36 h, reached maximal levels by 120 h, and remained elevated for the course of the study. These data indicate that inflammation leads to a rapid increase in hepatic ceruloplasmin mRNA content. This increase is largely the result of increased ceruloplasmin gene transcription, but comparison of the relative rate of transcription and mRNA accumulation suggests that changes in ceruloplasmin mRNA turnover are also involved. In addition, translational and/or post-translational mechanisms must account for the observed changes in serum ceruloplasmin concentration seen during inflammation.

Animals↗

PubMed1976

Ceruloplasmin: the copper transport protein with essential oxidase activity.

Ceruloplasmin, the blue copper-protein of vertebrate plasma, has been reviewed mainly from a functional point of view. However we have surveyed the chemistry and state copper in the molecule because of the implications of the recent data of Ryden (13,28). His observations suggest that unless special precautions are taken in the isolation of ceruloplasmin degradation, probably proteolytic, produces fragments of various sizes. When isolated, these fragments appear to be held together by noncovalent interactions. Comparison of their catalytic and spectral properties reveals no significant differences from a single homogeneous species of molecular weight of 134,000 isolated by Ryden's methods. On the other hand, the homogeneous molecule may differ in properties highly sensitive to conformation and three-dimensional parameters. Three types of copper atoms have been identified in ceruloplasmin, but their amino acid environment is still unknown. Ceruloplasmin possesses significant oxidase activity towards Fe(II) and numerous aromatic amines and phenols. Its ferroxidase activity has led to the discovery that it is a molecular link between copper and iron metabolism. Ceruloplasmin mobilizes iron into the plasma from iron storage cells in the liver. An equally important duty is that ceruloplasmin, after its rapid biosynthesis in the liver, serves as a major copper transport vehicle, comparable to transferrin. Evidence is accumulating that the copper atoms of ceruloplasmin are a prerequisite for copper utilization in the biosynthesis of cytochrome oxidase and other copper proteins. The ability of ceruloplasmin to release copper at specific cellular sites may be related to its broad substrate spectrum of biological reducing agents. A possible third role of ceruloplasmin is as a contributor to the regulation of the balance of biogenic amines through its oxidase action on the epinephrine and the hydroxyindole series. Thus ceruloplasmin is a copper-protein with several important functions, all of which are directly related to its oxidase activity.

Animals↗

PubMed2002

Ceruloplasmin levels in antineutrophil cytoplasmic antibody-positive patients.

Anti-myeloperoxidase (MPO) antibodies are associated with the development of anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis. The imbalance between the protease-antiprotease activity in the neutrophils has been implicated in the pathogenesis of ANCA-related vasculitis. Ceruloplasmin is an acute-phase protein that has antiproteinase and antioxidant properties and inhibits MPO activity. We attempted to study the association between serum ceruloplasmin and ANCA in childhood vasculitis. Forty-five ANCA-related diseases were included in the study. The age range was 4-16 years. Patients were divided into two groups based on indirect immunofluorescence and/or ELISA specificity (MPO). Twenty-six patients had p-ANCA- and 19 patients had c-ANCA-positive disease. Nine patients with Henoch-Schönlein purpura were studied as an ANCA-negative control group. Serum ceruloplasmin levels in p-ANCA-, c-ANCA-positive patients, and controls were 125.85+/-93.48 mg/dl, 59.79+/-17.60 mg/dl, and 64.34+/-18.77 mg/dl, respectively, and were significantly higher in patients with p-ANCA ( P<0.05). Ceruloplasmin levels were significantly decreased in remission ( P<0.05). Median MPO level in p-ANCA-positive patients was 15.2 (5-250) and was negative in all c-ANCA-positive patients. There was a significant positive correlation between MPO and ceruloplasmin levels ( r=0.70, P<0.05). Of 26 patients (53.8%) in the p-ANCA-positive group, 14 had renal involvement. The patients with renal disease had significantly higher ceruloplasmin levels than others (151.17+/-92.14 and 134.64+/-95.16 mg/dl respectively, P<0.05). In conclusion, the increase in ceruloplasmin levels during the acute phase suggests that this might be an activation criterion or a response to neutrophil-mediated tissue injury. Increased ceruloplasmin levels together with p-ANCA positivity may be predictive for renal involvement and a serious clinical course. The correlation between ceruloplasmin and MPO levels supports their association. Further studies are necessary to elucidate whether genetic and/or functional alterations in ceruloplasmin are effective in the pathogenesis of vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed2005

Identification of apo- and holo-forms of ceruloplasmin in patients with Wilson's disease using native polyacrylamide gel electrophoresis.

OBJECTIVES: To determine the serum ratio of holo-ceruloplasmin to total ceruloplasmin in patients with Wilson's disease (WD), we identified apo- and holo-forms of serum ceruloplasmin with native-PAGE electrophoresis. DESIGN AND METHODS: Serum obtained from nine patients with Wilson's disease was subjected to native-PAGE analysis. We also determined the ceruloplasmin level and ferroxidase activity in all of the samples. RESULTS: Among the nine patients, three had both forms of ceruloplasmin and six had only apo-ceruloplasmin. In the patients who had only apo-ceruloplasmin, the serum ceruloplasmin level was significantly lower than in the patients with both forms. CONCLUSIONS: Differences in the ability to incorporate copper into ceruloplasmin may have a role in ceruloplasmin concentrations in patients with Wilson's disease.

Adolescent↗