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PubMed1981

Iron mobilization and plasma ferroxidase factors in chickens.

Hematological values, metal content (Fe, Cu, Zn, Cd) in plasma and liver, ceruloplasmin (p-phenylendiamine oxidase) and ferroxidase activity in plasma, were analyzed in chicks, fed during 10 weeks on a commercial diet, supplemented by either 5,000 ppm Zn or 100 ppm Cd. A microcytic and hypochromic anemia was evident in both groups but in the Cd-fed chicks, plasma iron and ceruloplasmin values were normal. Estrogen administration mobilized iron in the Cd-group but not in the Zn-group. The precipitation of plasma phosvitin reduced (90%) the ferroxidase activity that had been previously induced by the estrogens. Correcting copper levels in the Zn-group, by copper injection, restored the ceruloplasmin level. However, the estrogens, in such birds, neither mobilized the plasma iron nor increased the ferroxidase activity. Plasma citrate was determined in laying, non-laying hens and in estrogenized or normal males. The contribution of citrate to the ferroxidase activity of plasma during the laying period, was negligible. It was concluded that plasma phosvitin during laying was the main factor responsible for the ferroxidase activity. However, the ceruloplasmin in chickens, could play a secondary role in iron mobilization.

Anemia, Hypochromic↗

PubMed1994

Construction of a ferroxidase center in human ferritin L-chain.

Ferritins are 24-mer proteins which store and detoxify intracellular iron. Mammalian ferritins are made of two subunit types, the H- and L-chains, with different functional specificity. The H-chain has a metal-binding site (the ferroxidase center) which confers ferroxidase activity to the protein and accelerates iron incorporation. In the L-chain the center is substituted by a salt bridge. We performed several site-directed mutageneses in the L-chain with the aim to construct the center and confer ferroxidase activity to the protein. Most variants were insoluble and did not refold into homopolymers, probably due to electrostatic repulsion introduced by the substitutions. However, they formed hybrids when they were renatured together with the L- or H-chains. The heteropolymers made of 90% L-chain and 10% of an L-variant with all the ligand residues of the H-chain center had 25-30% of the ferroxidase activity of the H-chain homopolymer. This corresponds to the activity of an H/L heteropolymer with 7% H-chain. It is concluded that: (i) it is possible to construct a ferroxidase center in the L-chain with an activity equivalent to that of the H-chain, (ii) the residues of the center interfere with the folding/assembly of the L-, but not of the H-chain, (iii) heteropolymers can be made even between ferritin subunits with large differences of refolding rates.

Amino Acid Sequence↗

PubMed2004

The relationship between haptoglobin polymorphism and serum ceruloplasmin ferroxidase activity.

The antioxidative potential of haptoglobin is type dependent; Hp2-2 has much lower antioxidative capacity than Hp1-1 or Hp2-1. It is therefore possible that other antioxidants may compensate for decreased antioxidative capacity in Hp2-2 individuals. Haptoglobin polymorphism was correlated with ceruloplasmin ferroxidase activity in a sample population of unrelated black Jordanians. Hp2-1 was the predominant type, occurring at a frequency of 0.518 and Hp2 was the common allele, occurring at a frequency of 0.6455; no Hp0-0 individuals were observed in the sample population. In general, haptoglobin concentration was highest among Hp1 homozygotes and lowest among Hp2 homozygotes, while ceruloplasmin ferroxidase activity was highest among Hp2 homozygotes and lowest among Hp1 homozygotes. Furthermore, ceruloplasmin ferroxidase activity was higher at haptoglobin concentrations >85 mg/dl compared with that at haptoglobin concentrations of 30-85 mg/dl, which was also higher than at haptoglobin concentrations <30 mg/dl, irrespective of haptoglobin type. These results suggest that ceruloplasmin ferroxidase activity is both haptoglobin type and concentration dependent.

Black People↗

PubMed1984

Purification and characterization of the serum ferroxidase inhibitor.

The inhibitor of the serum ferroxidases, recently detected in rabbit serum, has been purified to homogeneity from human serum by a combination of gel-filtration and ion-exchange chromatography. The molecular weight, chromatographic behavior, electrophoretic mobility, electrofocusing pH, carbohydrate content, and reactivity with anti-human albumin during immunodiffusion indicate that the ferroxidase inhibitor is serum albumin. Copper-binding studies, proteolytic fragmentation studies, and a comparison of the inhibitory potencies of several albumin species which differ in their affinity for copper strongly indicate that albumin elicits its inhibitory effect on the serum ferroxidases by interacting with the functional copper of these enzymes. Kinetic analyses further suggest that albumin competes with substrate (ferrous iron) for binding to the functional copper of the serum ferroxidases.

Blood Protein Electrophoresis↗

PubMed2003

Haptoglobin 2-2 phenotype is associated with decreased ferroxidase activity in smokers.

BACKGROUND: Cigarette smoking and the inheritance of Hp 2-2 phenotype have been separately linked to cardiovascular disease. In this study, the combined effects of smoking and the presence of Hp 2-2 type on predisposition to cardiovascular disease were investigated. METHODS: Fasting blood specimens were collected from 489 Jordanian males (228 smokers and 261 nonsmokers). Haptoglobin phenotype was determined by electrophoresis, and lipid profile and ferroxidase activity were determined by spectrophotometric methods. RESULTS: The results show that, irrespective of Hp type, total- and LDL-cholesterol levels were significantly higher in smokers compared with nonsmokers, while levels of HDL-cholesterol and ferroxidase activity were lower in smokers. There was no significant difference between the three Hp types in nonsmokers regarding the lipid profile and ferroxidase activity. In the smokers group, however, serum ferroxidase activity was significantly lower in individuals with Hp 2-2 type compared with that in Hp 1-1 and Hp 2-1 smoker individuals. Smokers with the Hp 2-2 type have significantly higher levels of total- and LDL-cholesterol and lower HDL-cholesterol levels compared with that in nonsmokers expressing the same Hp type. CONCLUSION: These findings demonstrate that smokers with Hp 2-2 phenotype have a decreased antioxidant capacity suggesting that smoking coupled with the inheritance of an Hp-2-2 type predispose to more oxidative stress and cardiovascular disease.

Adolescent↗

PubMed2000

The essential role of Glu-185 and Tyr-354 residues in the ferroxidase activity of Saccharomyces cerevisiae Fet3.

The structural determinants required for ferroxidase activity by the yeast multicopper oxidase Fet3 have been partially clarified by site-directed mutagenesis based on homology modeling. Glu-185 and Tyr-354 were substituted with Ala and Phe, respectively. Fet3 E185A retained ca. 5% residual ferroxidase catalytic efficiency, and almost 40% oxidase efficiency. On the other hand, Fet3 Y354F exhibited 50% residual efficiency as a ferroxidase and more than 70% as an oxidase. These results provide new insights in the mechanism of iron binding and oxidation by Fet3, establishing the essential role of Glu-185 and Tyr-354, and allowing to dissect ferroxidase from non-iron oxidase activity.

Catalysis↗

PubMed2002

Effects of ferroxidase activity and species on ceruloplasmin mediated iron uptake by BT325 cells.

In a previous study, we found that human ceruloplasmin (hCP) promotes iron uptake rather than release in BT325 cells, a human glioma cell line. In this study, we investigated the effect of ferroxidase activity of hCP and different species of ceruloplasmins on CP-mediated iron uptake by the cells. The cells were incubated for 30 min at 37 degrees C with 1 microM 59Fe2+ with or without 150 microg/ml of the untreated and the ferroxidase-defective hCPs (apohCP and heat-inactivated hCP) or different species of ceruloplasmins (human CP, rabbit CP and bovine CP). The untreated hCP induced a significant increase in iron uptake by BT325 cells, while ferroxidase-defective hCPs with (heat-inactivated hCP) or without cooper ions (apohCP) had no such role. The untreated hCP increases significantly internalized iron but not membrane-bound iron, implying that hCP stimulated iron entry into the cell rather than increased extracellular binding of iron to the cell surface. All species of ceruloplasmins could promote iron uptake by the cells and the difference in degree of stimulatory effect among them was insignificant. These results suggested that ferroxidase activity of hCP is essential for the hCP-mediated iron uptake process and also that CP-stimulated iron uptake is not associated with copper ions in the protein, and that the effect of ceruloplasmin on iron uptake by BT325 cells is not species specific.

Aged↗

PubMed1999

Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease.

Recent evidence suggest the implication of transition metals leading to overproduction of free radicals as a possible causal factor in the death of nigral cells associated to Parkinson's disease (PD). Iron depots in the basal ganglia of PD patients have been described; in addition, contents of nigral copper have been found decreased, while its concentration in cerebrospinal fluid (CSF) is raised, particularly the free form of the metal. To search for a possible link between altered copper concentrations and PD, we advanced the hypothesis that ferroxidase activity of ceruloplasmin is decreased in the CSF of PD patients. We studied 35 untreated PD patients, 14 L-3,4-dihydroxyphenylalanine (L-DOPA)-treated PD patients and 26 controls. Both CSF ferroxidase activity and CSF copper content were measured and correlated with the clinical stage of the disease. We found that untreated PD patients had a significant reduction of 40% in CSF ferroxidase while CSF copper was slightly increased as compared with both the values in L-DOPA-treated PD patients and controls. We also found that the fraction of copper linked to ferroxidase in untreated PD is inversely related to the clinical stage of the disease.

Aged↗

PubMed1985

The behaviour of caeruloplasmin in stored human extracellular fluids in relation to ferroxidase II activity, lipid peroxidation and phenanthroline-detectable copper.

No Cu(II) ion is measurable in human serum or synovial fluid by the phenanthroline assay. On storage of human serum or synovial fluid at 4 degrees C, phenanthroline-detectable copper appears, lipid peroxidation occurs, ferroxidase I activity declines and ferroxidase II activity rises, yet there is no fall in immunologically detectable caeruloplasmin. Storage of body fluids at -20 degrees C or -70 degrees C slows, but does not prevent, these deteriorative changes. It is suggested that the presence of low-molecular-mass Cu(II) ion complexes, ferroxidase II activity, "cytotoxic factors' and "immunosuppressive factors' in body fluids may be, in part or in whole, an artifact of the storage and handling of the fluids. A report [Blake, Blann, Bacon, Farr, Gutteridge & Halliwell (1983) Clin. Sci. 64, 551-553] that the caeruloplasmin present in rheumatoid synovial fluid is deficient in ferroxidase activity is shown to be such an artifact. It is strongly recommended that all such experiments be performed upon freshly taken fluid samples.

Arthritis, Rheumatoid↗

PubMed1983

Ferroxidase and ascorbate oxidase activities of caeruloplasmin in synovial fluid from rheumatoid patients.

1. The protein caeruloplasmin inhibits certain free radical reactions, in part probably due to its ability to oxidize Fe2+ into Fe3+ (ferroxidase activity). Since caeruloplasmin is present in synovial fluid from rheumatoid patients, we investigated its properties in relation to protection of the joint from damage by oxygen radicals produced by activated phagocytes. 2. The ferroxidase and ascorbate oxidase activities of serum from both normal and rheumatoid patients could be accounted for by the caeruloplasmin present, as determined immunologically. More caeruloplasmin is present in the serum of rheumatoid patients than in normal serum. 3. Synovial fluid from rheumatoid patients contains caeruloplasmin protein but its ferroxidase and ascorbate oxidase activities are abnormally low. It is suggested that ferroxidase deficiency contributes to radical damage in the rheumatoid joint.

Arthritis, Rheumatoid↗

PubMed1991

Mutated recombinant human heavy-chain ferritins and myelosuppression in vitro and in vivo: a link between ferritin ferroxidase activity and biological function.

Human heavy-chain (H-) ferritin muteins obtained by oligonucleotide site-directed mutagenesis, together with wild-type recombinant human H- and light-chain (L-) ferritins, were evaluated for in vitro effects on the suppression of human bone marrow myeloid progenitor cells and for in vivo effects on marrow and splenic myelopoiesis in C3H/HeJ mice. The 10 H-ferritin muteins exhibited alterations of various regions of the molecule, including ones exposed on the outer surface, on the inner cavity, and on the hydrophilic and hydrophobic channels and of the four-alpha-helix bundle forming the subunit structure. They were stable and were electrophoretically analogous to wild-type H-ferritin. The muteins showed in vitro and in vivo myelosuppressive activity analogous to wild type, except for mutein 222, which was totally inactive and which lacked ferroxidase activity. Recombinant human L-ferritin, devoid of ferroxidase activity, was also inactive as a suppressor. The results demonstrate that H-ferritin myelosuppressive and ferroxidase activities are linked. One possibility is that ferroxidase activity may interfere with the cellular uptake of transferrin iron that is needed for cell proliferation, an interpretation consistent with the presently described ability of hemin to overcome H-ferritin suppressive effects.

Animals↗

PubMed1989

Ferroxidase activity increases in the aqueous humor during the ocular inflammatory response.

Ferroxidase activity was increased in the aqueous humor from inflamed eyes compared to their uninflamed contralateral controls 24 h after intravitreal injection of 10 ng of endotoxin. Changes in ferroxidase activity and copper concentration paralleled each other indicating that the plasma copper transport protein ceruloplasmin (plasma ferroxidase) entered the inflamed aqueous humor from plasma through disrupted blood ocular barriers. The presence of ferroxidase activity would facilitate the removal of potentially damaging, free radical generating Fe+2. Therefore, plasma proteins may perform important protective functions in the inflamed intraocular fluids.

Animals↗

PubMed2004

Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice.

Hephaestin (Hp) plays an important role in intestinal iron absorption and is predicted to be a ferroxidase based on significant sequence identity to the serum multicopper ferroxidase ceruloplasmin. Here, we demonstrate that Hp has both amine oxidase and ferroxidase activity in cultured cells and primary intestinal enterocytes with the use of both gel and solution assays. The specificity of the activity is shown by immunoblotting, immunoprecipitation, and immunodepletion experiments. Surprisingly, the truncated hephaestin expressed in sex-linked anemia (sla) mice still has measurable, but decreased, oxidase activity. Molecular modeling of the truncated hephaestin suggests retention of a minimum catalytic core required for enzymatic activity. We suggest that hephaestin, by way of its ferroxidase activity, facilitates iron export from intestinal enterocytes, most likely in cooperation with the basolateral iron transporter, Ireg1.

Amine Oxidase (Copper-Containing)↗

PubMed1995

Vitamin C at concentrations observed in premature babies inhibits the ferroxidase activity of caeruloplasmin.

High concentrations of total vitamin C have been measured in the plasma of premature infants. At these concentrations ascorbic acid inhibited the ferroxidase activity of caeruloplasmin measured directly in vitro. The degree of inhibition was dependent on the ratio of ascorbic acid: caeruloplasmin. Values for the ratio of vitamin C: caeruloplasmin measured in premature babies would be predicted to inhibit ferroxidase activity by up to at least 80%. Ferroxidase activity measured in the plasma of premature babies increased from birth but was significantly lower than in plasma collected from adults (< 0.001). Plasma ferroxidase activity was correlated with plasma caeruloplasmin concentration and, in premature babies only, showed a negative correlation with the ratio of vitamin C to caeruloplasmin. High levels of vitamin C in premature babies may compromise antioxidant mechanisms and exacerbate oxidant damage.

Antioxidants↗

PubMed1988

Decreased ceruloplasmin ferroxidase activity in cigarette smokers.

Ceruloplasmin is one of the most important antioxidant proteins in serum. Ceruloplasmin functions as a ferroxidase that oxidizes iron to the Fe3+ state, thereby preventing Fe2+-catalyzed lipid peroxidation and cellular damage. Despite increased antigenic amounts of ceruloplasmin, cigarette smoker serum has previously been shown to exhibit significantly less antioxidant activity than non-smoker serum. We demonstrate that the decreased antioxidant activity of cigarette smoker serum may be explained by a decrease in ceruloplasmin ferroxidase activity. Smokers had a 14% decrease in serum ceruloplasmin ferroxidase activity (units per milliliter) compared with nonsmokers. There was a 24% decrease in ferroxidase activity per milligram of ceruloplasmin in smokers compared with nonsmokers (0.32 +/- 0.009 U/mg vs 0.42 +/- 0.020 U/mg, p less than 0.005). Smoker serum also contained significantly less ceruloplasmin-specific antioxidant activity than nonsmoker serum. These observations may explain the decrement in smoker serum antioxidant activity that could predispose cigarette smokers to increased oxidant injury.

Adult↗

PubMed1987

Serum ferroxidase I and II in uremic patients under conservative treatment and maintenance hemodialysis.

Serum ferroxidase I (ceruloplasmin) and ferroxidase II activities were studied in 49 uremic patients under conservative treatment, in 79 patients undergoing hemodialysis and in 56 healthy subjects, as controls. Ferroxidase I was significantly higher in both groups of patients. Ferroxidase II was significantly elevated only in patients undergoing chronic hemodialysis. The cause of this difference is not clear, but seems to be of considerable interest.

Adult↗

PubMed1995

Carbamylation inhibits the ferroxidase activity of caeruloplasmin.

The ferroxidase activity of caeruloplasmin (EC 1.16.3.1) is an important antioxidant defence mechanism in man. In chronic renal failure proteins become carbamylated as a result of reactions with urea-derived cyanate. We have therefore investigated the effects of carbamylation on the ferroxidase activity of caeruloplasmin. Increasing degrees of carbamylation produce a progressive impairment of ferroxidase activity measured using o-dianisidine as substrate, and the ability of caeruloplasmin to load ferrous iron onto ovotransferrin is reduced. Carbamylation of caeruloplasmin may contribute to reduced antioxidant capacity in patients with renal failure.

Ceruloplasmin↗

PubMed1995

Prooxidant iron and copper, with ferroxidase and xanthine oxidase activities in human atherosclerotic material.

Low density lipoproteins are highly sensitive to oxidation by copper salts, and such peroxidation is accompanied by macrophage scavenger receptor recognition. This study shows that fresh human atherosclerotic material (aneurysms and endarterectomies) can contain detectable amounts of redox active iron and copper that is chelatable from tissue homogenates. Such material is often prooxidant towards lipid peroxidation and deoxyribose degradation. Aneurysms and endarterectomies contain ferroxidase 1 activities, whereas only in aneurysms could caeruloplasmin be immunologically detected. Ferroxidase 2 activity, characteristic of a copper-oxidised lipoprotein complex, could not, however, be detected in any of the atherosclerotic samples. A third ferroxidase activity, attributable to xanthine oxidase, was present in several aneurysms and endarterectomies.

Arteriosclerosis↗