Ceruloplasmin inhibition

Human ceruloplasmin inhibits lipid autoxidation induced by ascorbate or inorganic Fe It is considered an acute-phase protein with a beneficial effect in inflammation . It was suggested that ceruloplasmin acts as a scavenger of OJ radicals, as it inhibited the reduction of Fe(III)-cytochrome c and of nitroblue tetrazolium in the presence of xanthine oxidase, acetaldehyde, and dioxygen as an OJ-generating system A mechanism without reduction of Cu , similar to that... 

A typical time course of PCL with luminol as the photosensitizer is shown in Figure 5, as blank. The presence of a water-soluble antioxidant leads to dose-dependent temporary inhibition of PCL. ACW (antioxidant capacity of water-soluble compounds) represents the effect of human blood plasma (2 p.L) on PCL all tested antioxidants, such as ascorbic acid, uric acid, Trolox, taurine, bilirubin, ceruloplasmin, etc., produced the same effects. 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

The storage role of (Cu,Zn)-SOD in seeds e.g. seems plausible, when the Cu-carrier function of ceruloplasmin is considered The lipophilic anti-inflammatory and anti-ulcer Cu-chelates could also raise the Cu concentration in certain tissues and thus enhance their lysyl oxidase activity. But especially Cu(acetylsalicylate)2 inhibited protine,2-oxoglutarate dioxygenase (EC 1.14.11.2) and lysine,2-oxoglutarate dioxygenase (EC 1.14.1.4), which are also important enzymes in the processing of collagen... 

In in vitro studies penicillamine inhibited angiotensin-con-verting enzyme (ACE) and carboxypeptidase (930). Penicillamine interferes with the functions of the copper-containing enzyme ceruloplasmin, and some of the penicillamine- and copper-containing complexes formed in vivo have a superoxide dismutase effect (931). In patients with scleroderma, penicillamine normalized collagen metabolism, by inhibiting beta-galactosidase activity (932). 

A second member of the ceruloplasmin family multicopper oxidases with six BCB domains was recently identified as the causative agent of sex-linked anemia (sla) in mice (Vulpe et al., 1993). It was named hephaes-tin and shown to be expressed mostly in the small intestine and the colon, where it is presumably involved in gastrointestinal iron uptake. Hephaes-tin displays a high level of sequence identity to ceruloplasmin and differs from it only by an additional C-terminal transmembrane domain, which anchors the protein to the cell membrane. A 582-nucleotide in-frame deletion in the mRNA for hephaestin sla mice has been identified compared to normal animals. The mice with such a mutation are unable to release iron from enterocytes (intestinal epithelial cells) into the circulation, which results in severe anemia. The GPI-anchored form of ceruloplasmin could potentially also mediate similar cellular iron efflux in the central nervous system. There is a transferrin-independent iron uptake system that requires Fe(III) to be reduced to Fe(II) at the cell surface for uptake to occur (DeSilva et al., 1996). Ceruloplasmin would oxidize Fe and prevent its uptake by this mechanism. Briefly, the role of ceruloplasmin is most likely to prevent excessive intracellular iron accumulation by tightly controlling iron efflux and inhibiting its uptake. 

In independent studies, Aprison et al. (A7) found among tryptophan metabolites that 3-hydroxyanthranilic acid was capable of inhibiting the oxidation of N,N-dimethyl-p-phenylendiamine by purified ceruloplasmin and serum oxidase. 

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. 

If one had to state an overall role of copper in the body, one might say oxygen metabolism. One major factor shared by both zinc and copper is that both metal ions occur bound to metallothionein. The function of metallothionein is not firmly established. Copper is bound to another protein, ceruloplasmin, which occurs in the cell and plasma. The function of this protein is not clear either. Zinc absorption, as iron absorption, is impaired by high levels of phytic acid. Copper absorption is not inhibited by phytic acid. The major route of excretion of both metal ions is fecal, rather than urinary. 

Certain metals have a profound influence on the activity of the enzyme. Copper in concentrations as low as those resulting from contamination of glassware and reagents will catalyze nonenzymatic oxidation of p-phenyl-enediamine. For this reason it was recommended that 10 M EDTA (ethylenediaminetetraacetic acid) be incorporated in the reaction mixture (B28). However, higher concentrations of EDTA inhibit the enzyme, and it has been suggested that EDTA may form a complex with copper in ceruloplasmin and thereby inactivate the enzyme (H20, K3). The addition of EDTA to the reaction mixture therefore may not be desirable. We found that by simply avoiding copper contamination, by the use of precautions necessary in copper determinations, the nonenzymatic oxidation of p-phenylenediamine slows to an imperceptibly low rate, and in this situation there is of course no need to add EDTA. 

The oxidants are products of normal cellular respiration that are normally counterbalanced by an antioxidant defense system that prevents tissue destruction. The antioxidants include superoxide dismutase, catalase, glutathione peroxidase, ceruloplasmin, and a-tocopherol (vitamin E). Antioxidants are ubiquitous in the body. Hy-peroxia produces toxicity by overwhelming the antioxidant system. There is experimental evidence that a number of drugs and chemicals produce lung toxicity through increasing production of oxidants (e.g., bleomycin, cyclophosphamide, nitrofurantoin, and paraquat) and/or by inhibiting the antioxidant system (e.g., carmustine, cyclophosphamide, and nitrofurantoin). ... 

Ceruloplasmin is involved in the oxidation of iron and has also been involved in the oxidation of divalent manganese ion to the trivalent state (Gibbons et al. 1976). Selective inhibition of this oxidative function may be a method of mitigating the toxic effects of exposure to manganese. However, inhibition of the oxidation of manganese might also result in adverse effects on transport and cellular uptake of other... 

It was also found that inhibition of both T-lymphocytes and T-helper cells by penicillamine and Cu(II)sulphate or ceruloplasmin could not be blocked by Cu-Zn SOD but was completely blocked by catalase, suggesting mediation of inhibition by hydrogen peroxide [655]. Mononuclear phagocytes, which were not inhibited by the combination of penicillamine and Cu(II)sulphate, were found to protect T-lymphocytes from this mixture as well as hydrogen peroxide, and the protective factor was found to be a soluble fraction of human monocyte or erythrocyte lysates. 

The inhibitory eflFects of trivalent and other metal ions on ferroxidase (ceruloplasmin) activity were investigated by Huber and Frieden (6J) and the results are summarized in Tables VI and VII. All trivalent cations tested inhibited ferroxidase activity but the strong trivalent inhibitors had an ionic radius of 0.81 A or less. The inhibition by Al(III) was mixed competitive and uncompetitive with respect to the substrate, Fe(II). The uncompetitive portion of the inhibition was not the result of competition by Al(III) with the other substrate, oxygen. A mechanism for the mixed inhibition by Al(III) was proposed consistent with these... 

Ceruloplasmin (Cp), secreted into the blood stream, appears to be ubiquitous in vertebrates. There is extensive in vitro evidence that Cp efficiently catalyzes the oxidation of Fe to Fe under near physiological conditions. The role of Cp in iron metabolism is widely accepted and there is strong evidence for a secondary role in copper transport/regulation. Defects in hepatic biosynthesis of Cp may result in diseases such as Wilson s disease. There is conclusive evidence that Cp is the source for the copper found in cytochrome c oxidase and CuZn-SOD in cells. Cp inhibition of Fenton chemistry-induced oxidative damage of deoxyribose, lipids, and DNA points to an antioxidant role, which would explain the increase in Cp concentration in response to acute infection or inflammation. 

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