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PubMed1997

One-electron reduction of chromium(VI) by alpha-lipoic acid and related hydroxyl radical generation, dG hydroxylation and nuclear transcription factor-kappaB activation.

Reaction of chromium(VI) with alpha-lipoic acid (reduced form, also called 1,2-dithiolane-3-pentanoic acid) generated Cr(V) and hydroxyl radical (*OH) as measured by electron spin resonance and ESR spin trapping. 5,5-Dimethyl-1-pyrroline was used as a spin trapping agent. Catalase inhibited the *OH generation and enhanced the Cr(V) formation. Superoxide dismutase had an opposite effect. H2O2 enhanced the *OH generation and decreased the Cr(V) formation in a dose-dependent manner. Metal chelators, EDTA, diethylenetriaminepentaacetic acid, deferoxamine, and 1, 10-phenanthroline inhibited *OH radical generation in the order of EDTA > 1,10-phenanthroline > DTPA > deferoxamine. Oxygen consumption measurements indicated that molecular oxygen was used to generate *OH radical in the mixture of Cr(VI) and alpha-lipoic acid. H2O2 and superoxide radical (O2-) were involved as reactive intermediates. The *OH radical was generated via Cr(V)-mediated Fenton-like reaction (Cr(V) + H2O2 --> Cr(VI) + OH- + *OH). HPLC measurements show that the *OH radical generated by this reaction is capable of generating 8-hydroxyl-2'-deoxyguanosine from 2-deoxyguanosine. Incubation of Cr(VI) with cultured Jurkat cells resulted in an activation of DNA binding activity of the nuclear factor (NF)-kappaB. Addition of alpha-lipoic acid enhanced the NF-kappaB activation, while the *OH radical scavenger, sodium formate, inhibited it, showing that alpha-lipoic acid enhanced Cr(VI)-induced NF-kappaB activation via free radical reactions. The results indicate that while alpha-lipoic acid is considered to be an antioxidant, it may be a cellular one-electron Cr(VI) reductant and could be involved in the mechanism of Cr(VI)-induced carcinogenesis.

Antioxidants↗

PubMed1996

S-[(1 and 2)-phenyl-2-hydroxyethyl]-cysteine-induced cytotoxicity to rat renal proximal tubules.

S-[(1 and 2)-phenyl-2-hydroxyethyl]-glutathione is nephrotoxic in rats through its metabolic conversion to corresponding cysteine-S-conjugate, e.g., S-[(1 and 2)-phenyl-2-hydroxyethyl]-cysteine (PHEC). The present study was carried out to determine the mechanism of PHEC-induced toxicity in isolated rat renal proximal tubules. PHEC decreased tubule viability in concentration (0-2 mM)- and time (0-3 hr)-dependent manner, with initial decreases occurring 2 hr after exposure. Tubule basal and nystatin-stimulated oxygen consumption decreased before cell death following exposure to 0.5 and 1 mM PHEC. Assessment of direct mitochondrial function within the proximal tubules showed that respiration was reduced in the absence and presence of a phosphate acceptor using site II (succinate) and site I (malate/glutamate) respiratory substrates 30 and 45 min after exposure to 0.5 and 1 mM PHEC. Exposure of proximal tubules to 1 mM PHEC caused a time-dependent decline of mitochondrial membrane potential (as measured by the uptake of the cationic fluorescent dye, rhodamine 123 by the proximal tubules) and depletion of ATP content with initial decrease occurring as early as 30 min after the exposure. Glutathione depletion and lipid peroxidation occurred within 90 min clearly preceding cell death after exposure to 0.5 and 1 mM PHEC. Pretreatment with 1 mM deferoxamine prevented PHEC-induced lipid peroxidation but did not prevent PHEC-induced cytotoxicity, whereas deferoxamine pretreatment prevented lipid peroxidation, mitochondrial dysfunction, and cytotoxicity after exposure to 0.5 mM tertiary-butyl hydroperoxide, suggesting that iron-mediated lipid peroxidation does not contribute to PHEC-induced proximal tubule cell death. Pretreatment of renal proximal tubules with 10 mM fructose failed to prevent the change in mitochondrial membrane potential, the ATP depletion and cytotoxicity caused by 1 mM PHEC, indicating that the glycolytic pathway is not important in renal proximal tubule respiration and cell injury. Pretreatment of renal tubules with aminooxyacetic acid failed to prevent the mitochondrial dysfunction induced by 1 mM PHEC, indicating an absence of further metabolism of PHEC by a beta-lyase-dependent pathway. It is therefore proposed that the alteration of mitochondrial functions and the consequent loss of cellular energy supplies can represent the mechanisms by which PHEC expressed its acute cytotoxicity.

Animals↗

PubMed1991

Pulmonary mucormycosis presenting as massive fatal hemoptysis in a hemodialytic patient with chronic renal failure.

A 38 year old female patient died following massive hemoptysis occurring during maintenance hemodialysis for chronic renal failure. In addition to renal dysfunction, laboratory data showed low levels of serum immunoglobulins; chest X-rays did not reveal any abnormal shadows. For the last 11 months, the patient had not received deferoxamine. At autopsy, major bronchi were plugged with coagulated blood. Irregular thickening of the right main bronchial wall close to the lung hilus was noted. Light microscopic examination disclosed mycotic granulomata in the bronchial wall, where the pulmonary arterial wall was also involved. Immunostaining using specific antibody identified Mucor hyphae. The mucormycosis is a serious complication of chronic renal failure and hemodialysis. In the current case, it is likely that immune dysfunction rather than deferoxamine was the important predisposing factor to the growth of the fungus.

Adult↗

PubMedDate not supplied

Effect of oxidants on Na,K,ATPase and its reversal.

Ischemia-reperfusion heart cell injury may be mediated, at least in part, through the generation of oxy radicals. Therefore, mechanisms of action of two oxidants on a membrane model, partially purified Na,K,ATPase, were investigated. Effects of H2O2, an oxygen intermediate postulated to play a primary role in reperfusion injury, on the function of the enzyme were time-dependent and potentiated by Fe ions. The inhibition of enzyme activity was prevented by chelators, but not by hydroxyl radical scavengers. The results support the view that the possible mode of enzyme modification involves H2O2-derived, Fe ion-catalyzed, localized ("site-specific") hydroxyl radical formation. The action of hypochlorous acid (HOCl), a powerful oxidant postulated to be produced by activated neutrophils, was quantitatively similar to that of H2O2 plus Fe ions in causing enzyme dysfunction. This is partly because relatively large doses of oxidants were required, due to the presence of physiological anti-oxidant defense mechanisms in the membrane. Although a combination of deferoxamine (Fe ion chelator) and dithiothreitol (DTT) (sulfhydryl reducing agent) was most effective in preventing the enzyme modification, once enzyme inactivation by oxidants is in progress, deferoxamine plus DTT could only arrest further deterioration of the enzyme function. Therefore, the oxidant-induced change in membrane dysfunction advances with time; the advance can be stalled, but the enzyme activity cannot be restored to normal.

Adenosine Diphosphate↗

PubMed1991

Aluminum effect on the activity of superoxide dismutase and of other antioxygenic enzymes in vitro.

The effect of Al on superoxide dismutase (SOD) and on other antioxygenic enzymes: horseradish peroxidase, catalase, and glutathione peroxidase, has been investigated in vitro. In the case of SOD, the effect of metal chelators (EDTA and deferoxamine) and a possible synergistic effect with iron salts have also been tested using the pyrogallol assay. There is no significant inhibitory effect of Al on the activity of any of the above-mentioned enzymes. Noticeable increases in SOD activity were observed when metal chelators were added to the medium, but not when high concentrations of Al were present too, in the case of deferoxamine (DFO). The former fact seems to be a consequence of the chelation of transition metal ions that catalyze pyrogallol autoxidation by a mechanism not inhibitable by SOD, interfering in its action, which may account for part of the DFO antioxidant effect observed in vivo. The latter phenomenon could be owing to a saturation of the chelating capacity of DFO by an excess of Al present in the medium, which should bring the system back to the interfering conditions explained above. It can be concluded that Al, either in the presence or in the absence of iron salts, does not inhibit SOD activity in vitro. Moreover, no significant binding of Al to SOD was demonstrated, and the amounts of its metal constituents, Cu and Zn, were not affected by preincubation of the enzyme with Al. The effect of the different compounds tested on the rate of autoxidation of the indicating scavenger, pyrogallol, and a suitable hypothesis on their role in the oxidation process are also discussed.

Aluminum↗

PubMed2003

GTP gamma S increases Nav1.8 current in small-diameter dorsal root ganglia neurons.

Tetrodotoxin-resistant (TTX-R) sodium current in small-size dorsal root ganglia (DRG) neurons is upregulated by prostaglandin E(2) and serotonin through a protein kinase A (PKA)/protein kinase (PKC) pathway, suggesting G protein modulation of one or more TTX-R channels in these neurons. Recently, GTP(gammaS), a hydrolysis-resistant analogue of GTP, was shown to increase the persistent current produced by the TTX-R Na(v)1.9. In this study, we investigated the modulation of another TTX-R channel, Na(v)1.8, by GTP(gammaS) in small-diameter DRG neurons from rats using whole-cell voltage clamp recordings. Because it has been suggested that fluoride, often used in intracellular recording solutions, may bind to trace amounts of aluminum and activate G proteins, we recorded Na(v)1.8 currents with and without intracellular fluoride, and with the addition of deferoxamine, an aluminum chelator, to prevent fluoride-aluminum binding. Our results show that GTP(gammaS) (100 micro M) caused a significant increase in Na(v)1.8 current (67%) with a chloride-based intracellular solution. Although the inclusion of fluoride instead of chloride in the pipette solution increased the Na(v)1.8 current by 177%, GTP(gammaS) further increased Na(v)1.8 current by 67% under these conditions. While the effect of GTP(gammaS) was prevented by pretreatment with H7 (100 micro M), a non-selective PKA/PKC inhibitor, the fluoride-induced increase in Na(v)1.8 current was not sensitive to H7 (100 micro M), or to inclusion of deferoxamine (1 mM) in the intracellular solution. We conclude that G protein activation by GTP(gammaS) increases Na(v)1.8 current through a PKA/PKC mechanism and that addition of fluoride to the pipette solution further enhances the current, but is not a confounding variable in the study of Na(v)1.8 channel modulation by G proteins independent of a PKA/PKC pathway or binding to aluminum.

Action Potentials↗

PubMed2001

Intracellular oxidative modification of low density lipoprotein by endothelial cells.

We investigated intracellular oxidative modification of low density lipoprotein (IOM-LDL) by endothelial cells (ECs) and the role of ferritin in this process. IOM-LDL was examined by immunocytochemistry with an anti-oxidized phosphatidylcholine antibody and by lipid peroxidation assay. Incubation of LDL-treated ECs (human umbilical vein endothelial cells, passage 3) with ferritin produced cytoplasmic immunostain with the antibody, especially in large or giant ECs, and the formation of thiobarbituric acid-reactive substance (TBARS) in these cells. These observations suggest that ECs can perform IOM-LDL. Incubation with the iron chelator deferoxamine or pretreatment of LDL-treated ECs with deferoxamine suppressed ferritin-induced IOM-LDL by greater than 60%. Antioxidants dimethylsulphoxide and butylated hydroxytoluene markedly inhibited IOM-LDL, but mannitol did so only mildly. Catalase and superoxide dismutase had little or no effect on IOM-LDL. Apoferritin substituted for ferritin did not induce IOM-LDL. Our data suggest that IOM-LDL is mediated by intracellular hydroxyl radical formation, which is catalyzed mainly by free iron released from ferritin, and that ECs contribute to the development of atherosclerosis via IOM-LDL.

Cells, Cultured↗

PubMed1993

Roles for oxidative stress and poly(ADP-ribosyl)ation in the killing of cultured hepatocytes by methyl methanesulfonate.

The mechanisms by which the methylating agent methyl methanesulfonate (MMS) kills cultured hepatocytes were studied. In an amino-acid-free Krebs-Ringer buffer (KRB), 1 mM MMS depleted the cells of glutathione (GSH) within 1-2 hr. Lipid peroxidation, as measured by the accumulation of malondialdehyde (MDA), followed, and over 70% of the cells died within 3-4 hr. The iron chelator deferoxamine and the antioxidant N,N'-diphenyl-1,4-phenylenediamine (DPPD) prevented lipid peroxidation and death of the hepatocytes without any effect on the loss of GSH. 3-Aminobenzamide (ABA), a poly(ADP-ribose) polymerase inhibitor, also prevented the cell killing by attenuating the loss of GSH. In a culture medium containing amino acids and antioxidants (Williams' E medium, WEM), 1 mM MMS killed the hepatocytes more slowly, with 70% of the cells dying 8-12 hr after treatment. Lipid peroxidation accompanied the loss of viability. Deferoxamine and DPPD inhibited lipid peroxidation, while only partially protecting against the cell killing. ABA offered more protection and reduced the decline of GSH and decreased lipid peroxidation. ABA also reduced the extent of the depletion of both NAD and ATP that accompanied the cell killing by MMS in WEM. These data indicate that MMS killed the hepatocytes by different mechanisms depending on the culture conditions. In KRB, the toxicity of MMS was a consequence of oxidative cell injury that follows the depletion of GSH. In WEM, both oxidative injury and the action of poly(ADP-ribose) polymerase in response to DNA single-strand breaks contributed to the loss of viability.

Amino Acids↗

PubMed1989

Growth-stimulating effect of transferrin on a hybridoma cell line: relation to transferrin iron-transporting function.

The relation of the growth-stimulating capacity of transferrin to its iron-transporting function was investigated in mouse hybridoma PLV-01 cells cultivated in a chemically defined medium. The cells were precultivated in protein-free medium supplemented either with ferric citrate (cells with a high intracellular iron level) or with iron-saturated transferrin (cells with a low intracellular iron level). Iron uptake was monitored after the application of 59Fe-labeled ferric citrate or pig transferrin. Cultivation of the cells at the optimum growth-stimulating concentration (500 microM) of ferric citrate resulted in an intracellular iron level about 100-fold higher than that of cells cultivated at the optimum transferrin concentration (5 micrograms/ml). Replacement of pig transferrin with bovine transferrin resulted in similar intracellular iron levels, but the growth-stimulating effect of bovine transferrin was more than one order of magnitude lower. Cells with a high intracellular iron level grew equally well when cultivated with iron-saturated transferrin or with apotransferrin + deferoxamine (2 micrograms/ml). On the other hand, cells with a low intracellular iron level required iron-saturated transferrin for further growth and apotransferrin + deferoxamine was ineffective. The results suggest that transferrin can act as a cell growth factor only in the iron-saturated form. However, several findings of this work indicate that supplying cells with iron cannot be accepted as the full explanation of the transferrin growth-stimulating effect.

Animals↗

PubMed1989

The role of metal ions in ischemia/reperfusion injury in skin flaps.

The role of hydroxyl radical generation by the metal-catalyzed Haber-Weiss reaction in producing injury to postischemic skin flaps in rats was evaluated. The venous drainage from groin island flaps was occluded for 7 hr and then reperfused. The flaps were infused with either deferoxamine, CaNa2EDTA, histidine, salicylate, or vehicle (saline) at the time of reperfusion. In another experimental group, the role of hydrogen peroxide was evaluated by the infusion of catalase at the time of reperfusion. Treatment with a single dose of deferoxamine (40 mg/kg), CaNa2EDTA (50 mg/kg), or histidine (50 mg/kg), significantly increased the flap survival rate from 24 to 63, 75, and 63%, respectively. A large dose of salicylate (80 mg/kg) improved the flap survival rate (to 63%): a smaller dose (40 mg/kg) offered no improvement. A large dose of catalase ameliorated the survival rate (to 88%). The results suggest that the presence of metal ions is required for the expression of free radical-induced tissue damage. Hydrogen peroxide appears to be essential for the production of this injury.

Animals↗

PubMed1990

Sensitivity of the sodium efflux in single barnacle muscle fibers to the microinjection of aluminum.

A study has been made of the behavior of the Na efflux in single muscle fibers from the barnacle, Balanus nubilus, toward the microinjection of AlCl3. The effect of microinjecting AlCl3 is either biphasic with inhibition following transitory stimulation, or monophasic with inhibition occurring promptly and taking about 1 hr to reach a maximum. The magnitude of the inhibition is dose dependent and the minimally effective concentration is 10 mM. This is diluted by the myoplasm by a factor of roughly 100. Fibers injected with 1 M AlCl3 are found to be insensitive to 10(-4) M ouabain, whereas fibers injected with 0.5 M AlCl3 show a further fall in Na efflux, which is smaller than that seen in control fibers. The response of the ouabain-insensitive Na efflux to the injection of 0.5 M AlCl3 is biphasic: stimulation is followed by inhibition. The stimulatory phase is largely dependent on the presence of external Ca2+ and is reversed by the sudden omission of Ca2+ from the bathing medium. Fibers also injected with 0.5 M AlCl3 show a marked reduction in the response of the Na efflux to high external K. Injection of ATPMg before or after the injection of AlCl3 fails in most instances to abolish or reverse the inhibitory effect. By contrast, fibers preinjected with deferoxamine show little or no effect following the injection of AlCl3. However, external application of deferoxamine is ineffective.

Aluminum↗

PubMed1991

Mitochondrial dysfunction is an early event in ochratoxin A but not oosporein toxicity to rat renal proximal tubules.

Ochratoxin A (OA) and oosporein (OSN) are two mycotoxins that may cause nephrotoxicity through either mitochondrial dysfunction or lipid peroxidation. Using isolated rat renal proximal tubules in suspension, the cellular events preceding OA- or OSN-induced cytotoxicity were investigated. OA and OSN decreased tubule viability in a concentration (0-1 mM)- and time (0-4 hr)-dependent manner, with initial decreases occurring 1 hr after exposure. Tubule basal and nystatin-stimulated oxygen consumption decreased before cell death after OA (0.5 and 1 mM) and 0.25 mM t-butyl hydroperoxide (TBHP) exposure, but did not decrease after OSN exposure (0.25-1 mM). The oxidant TBHP was used as a positive control in these studies. Direct probing of mitochondrial function within proximal tubules confirmed the toxicity of OA to mitochondria. Respiration was reduced in the absence and presence of a phosphate acceptor using site I (glutamate/malate) and site II (succinate) respiratory substrates 15 and 30 min after exposure to 1 mM OA. Lipid peroxidation preceded cell death after exposure to 1 mM OA and 0.25 mM TBHP, but did not occur after exposure to 1 mM OSN. Deferoxamine (1 mM) pretreatment before the addition of 1 mM OA or OSN prevented OA-induced lipid peroxidation, but did not prevent OA- or OSN-induced cytotoxicity. In contrast, deferoxamine pretreatment prevented lipid peroxidation, mitochondrial dysfunction, and the loss of tubule viability after exposure to 0.25 mM TBHP. This study shows that mitochondrial dysfunction is an early event during the development of OA toxicity, but not in OSN-induced toxicity. Furthermore, iron-mediated lipid peroxidation does not contribute to OA- or OSN-induced proximal tubule cell death.

Animals↗

PubMed1985

Protection of mice against the lethal effects of sodium metavanadate: a quantitative comparison of a number of chelating agents.

10 Chelating agents were administered to mice by intraperitoneal (i.p.) injection in order to compare their relative effectiveness in preventing death after a single i.p. injection of NaVO3. Ascorbic acid, Tiron (4,5-dihydroxy-1,3-benzene-disulfonic acid) and deferoxamine were the most effective antidotes for acute NaVO3-toxicity. The therapeutic index of ascorbic acid against 0.61 mmol/kg NaVO3 was found to be 95.2. This was 4.6 and 12.2 times greater than those of Tiron and Deferoxamine respectively. L-Cysteine greater than Na2CaEDTA greater than Na3CaDTPA reduced the acute mortality of mice following i.p. injection of NaVO3. Sodium salicylate, D,L-penicillamine, DMSA and DDC were not effective as antidotes for acute NaVO3-toxicity.

Animals↗

PubMed1986

Comparative studies using 125I- and 111In-labeled monoclonal antibodies.

HDP-1 monoclonal antibody was labeled with 111In using deferoxamine, diethylenetriaminepentaacetic acid or 1-(para-bromoacetamidobenzyl)-EDTA as chelating agents or with 125I. The in vitro binding capacity and stability of the labeled molecules were evaluated using affinity chromatography. The biodistribution and imaging capabilities were compared using an animal model system that does not involve the use of tumors. Similar studies were done using the corresponding labeled F(ab')2 and Fab' fragments. All labeled molecules, except those treated with deferoxamine, were stable in vitro. When tested in vivo, all retained their capacity to localize in the target tissue (lung). The lung %ID/g levels for the 111In-labeled molecules were, however, slightly lower than those observed for the corresponding 125I-labeled molecules. High uptake was also observed in the liver or kidneys when the 111In-labeled molecules were used; no such results were obtained with the 125I-labeled molecules. More work appears to be necessary before the use of bifunctional chelates becomes the optimal method for radiolabeling monoclonal antibodies for use in tumor imaging.

Animals↗

PubMed1993

Demonstration of hydroxyl radical and its role in hydrogen peroxide-induced myocardial injury: hydroxyl radical dependent and independent mechanisms.

We investigated the mechanism of hydrogen peroxide (H2O2) action on myocardial injury in relation to hydroxyl radical (.OH) formation. Isolated rat hearts were perfused with a concentration of H2O2 (300 microM) known to produce cardiac injury. Perfusion of H2O2 for 15 min caused severe myocardial dysfunction, morphological damage, ATP depletion, and lipid peroxidation. Hydrogen peroxide concentration in the coronary effluent was reduced approximately 40% reflecting a myocardial H2O2 consumption of 12.7 +/- 0.9 mumol/15 min/g wet tissue (n = 12). One of the .OH-generated derivatives, 2,3-dihydroxybenzoic acid (2,3-DHBA), formed from reaction with salicylic acid, was detected in the coronary effluent by high-performance liquid chromatography at 23.16 +/- 4.05 nmol/15 min/g wet tissue. Catalase (200 U/ml, n = 6) added to the perfusate attenuated all parameters of myocardial injury by eliminating H2O2 from the perfusate, and thus .OH was not detected in the effluent. Deferoxamine (5 mM, n = 7) added to the perfusate reduced morphological damage and lipid peroxidation, but not dysfunction or ATP depletion. Deferoxamine significantly reduced .OH production; 2,3-DHBA was 5.22 +/- 3.56 nmol/15 min/g wet tissue. The present study provides evidence that .OH is produced in the H2O2-perfused heart. The adverse H2O2-mediated myocardial outcomes documented in this study appear to arise from both .OH-dependent and .OH-independent mechanisms.

Adenosine Triphosphate↗

PubMed1990

Effect of sodium fluoride on cytosolic free Ca2(+)-concentrations and cGMP-levels in endothelial cells.

Sodium fluoride was used to investigate a possible involvement of G-proteins in the regulation of endothelial calcium channels. Incubation of cultured porcine aortic endothelial cells with sodium fluoride produced a dose-dependent increase in intracellular free calcium (EC50 approximately 5 mM). The effect strictly depended on the presence of extracellular CaCl2, indicating an enhanced influx of extracellular Ca2+ rather than a release of Ca2+ from intracellular stores. The Al3+ chelator deferoxamine abolished the stimulatory effect of sodium fluoride but did not interfere with the stimulatory effect of bradykinin. These data confirm the current hypothesis that the complex AlF-4 and not the fluoride anion activates G-proteins and exclude a direct inhibitory effect of deferoxamine on Ca2(+)-uptake. In contrast to isoproterenol and 5'-N-ethylcarboxamido-adenosine (NECA), which elevated endothelial cAMP-levels without affecting intracellular Ca2(+)-concentrations, sodium fluoride was not able to increase endothelial cAMP. This indicates that the effect of sodium fluoride on endothelial Ca2(+)-levels is not due to stimulation of a Gs-protein. Similar to its effect on cytoplasmic Ca2+, sodium fluoride also increased endothelial cGMP-levels which has recently been suggested to serve as biochemical marker for the formation of endothelium derived relaxing factor (EDRF). Thus, similar to the activation of receptor operated calcium channels, direct stimulation of a G-protein by sodium fluoride results in an increase of cytoplasmic Ca2+ and the formation of EDRF.

Animals↗

PubMed2004

Iron chelation therapy in sickle-cell disease and other transfusion-dependent anemias.

Regular red cell transfusion therapy may be life-saving or may reduce complications substantially in several hematological disorders. The inevitable consequence of repeated transfusions is iron loading, which, if untreated, leads to organ failure and death. Chelation therapy with deferoxamine is the standard of care for patients who have transfusional iron overload. The necessity to administer this drug parenterally limits compliance; this has prompted the search for a safe and effective orally-administered chelator. Deferiprone, the first extensively studied orally active chelator, is now licensed for use in Europe for patients who are unable to use deferoxamine effectively or safely. ICL670, a newer oral chelator, is being tested in large clinical trials. Combined therapies, potentially including transfusional methods to reduce iron loading with parenteral and oral chelators, may improve compliance and efficacy in some patients who are transfused chronically.

Anemia↗

PubMed2004

Copper-induced formation of reactive oxygen species causes cell death and disruption of calcium homeostasis in trout hepatocytes.

We have previously shown that copper is acutely toxic for trout hepatocytes, inducing enhanced influx of Ca(2+) and a loss of cell viability. The aim of the present study was to elucidate the pathways of Ca(2+) entry into the cells, the hypothetical role of reactive oxygen species (ROS) in copper toxicity, and the interaction of ROS formation and the disruption of Ca(2+) homeostasis. We found that, acutely, copper-induced cell death occurred independently from an increase of intracellular free Ca(2+) (Ca(2+)i), but could be prevented by addition of agents interfering with ROS production. Addition of the Ca(2+) channel blocker verapamil did not affect the Ca(2+)i increase evoked by copper, whereas in the presence of LaCl(3), an inhibitor of both Ca(2+) channels and Na(+)/Ca(2+)-exchange, this increase was significantly delayed. ROS formation, estimated by use of the fluorescence indicator 2',7'-dichlorofluorescin diacetate, was significantly enhanced by copper. Omission of extracellular Ca(2+) or addition of either verapamil or LaCl(3) did not diminish ROS formation induced by copper. In contrast, the hydroxyl radical scavenger dimethyl sulfoxide and the ferric ion chelator deferoxamine inhibited radical production. In addition, these agents either partially (dimethyl sulfoxide) or completely (deferoxamine) prevented an increase of Ca(2+)i. Altogether our results indicate that ROS formation is the crucial event leading to cell death during acute exposure to copper, whereas the increase of Ca(2+)i is a secondary, acutely less toxic, phenomenon. Furthermore, these findings suggest that Ca(2+) entry occurs via a LaCl(3)-sensitive pathway, presumably representing Na(+)/Ca(2+)-exchange, and non-specific membrane leaks induced by lipid peroxidation in the presence of copper.

Animals↗