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PubMed1993

Role of iron and superoxide in mediating hydrogen peroxide injury to cultured rat gastric cells.

BACKGROUND: Gastric epithelium is exposed to toxic, reactive oxygen species generated within the lumen. The present study examined the role of cellular iron and superoxide (O2-) in mediating hydrogen peroxide (H2O2)-induced damage to cultured gastric mucosal cells. METHODS: H2O2 was generated by glucose oxidase acting on b-D(+)glucose. Cytotoxicity was assessed by 51Cr release from prelabeled cells. RESULTS: Deferoxamine (a chelator of Fe3+) prevented injury induced by H2O2, whether present before or during H2O2 production. In contrast, whereas the presence of phenanthroline (a chelator of Fe2+) during the cytotoxicity assay prevented damage, prior treatment with the agent did not; this suggested that cellular Fe3+ reduced to Fe2+ upon exposure to H2O2 is responsible for damage. Neither extracellular superoxide dismutase nor inhibitors of xanthine oxidase (a possible source of cellular O2- production) protected against H2O2. Further, protection by iron chelators was not associated with modulation of endogenous antioxidants. CONCLUSIONS: Deferoxamine and phenanthroline protect cells from H2O2 by chelating stored iron (Fe3+) or reduced iron (Fe2+), respectively. Reduction of cellular Fe3+ appears to be a prerequisite for mediation of damage, but this reduction is independent of extracellular O2- or cellular xanthine oxidase-derived O2-.

Allopurinol↗
PubMed1990

Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains.

Since hydrogen peroxide (H2O2) can react with ferrous iron (FE++) to form the more toxic hydroxyl radical (OH) in vitro, and since H2O2 is generated brain xanthine oxidase (XO) during ischemia/reperfusion (I/R), we hypothesized that gerbils depleted of iron by dietary restriction or treated with iron chelators would be less susceptible to I/R injury. We found that gerbils fed a low iron diet for 8 weeks had decreased brain and serum iron levels, less neurologic deficits, and decreased brain edema after temporary unilateral carotid ligation (ischemia) and then reperfusion than gerbils fed a control standard iron diet. In addition, brains from gerbils treated with iron-free deferoxamine (an iron chelator), but not iron-loaded deferoxamine, had decreased (P less than .05) brain edema following ischemia and reperfusion. The results indicate that iron may contribute to cerebral ischemia/reperfusion damage.

Animals↗
PubMed1991

Renal preservation after warm ischemia using oxygen free radical scavengers to prevent reperfusion injury.

Oxygen free radicals damage kidneys and accumulate during the period of preservation prior to transplantation. We hypothesized that a perfusate containing either an oxygen free radical scavenger such as ceruloplasmin, or an iron-chelating agent such as deferoxamine, would improve kidney preservation. Thirty-eight mongrel dogs underwent autotransplantation of the left kidney after 30 min of warm ischemia and 48 hr of machine perfusion (MOX-100, Water Instruments, Rochester, MN) at 5 degrees C and pH of 7.4. The right kidney was removed at the time of autotransplantation. Four blind code-labeled preservation solutions were tested. SGF-I was used for the control group (Group 1, n = 13), and the remaining animals were transplanted with kidneys preserved with one of three solutions modified from the basic SGF-I solution: Group 2, SGF-I plus deferoxamine (656 mg/liter), n = 8; Group 3, SGF-I ceruloplasmin enriched (72 mg/dl), n = 8; and Group 4, SGF-I ceruloplasmin reduced (3.4 mg/dl), n = 9. Serum creatinine levels were measured daily for 2 weeks and survival curves for each of the four groups were estimated by the Kaplan-Meier method. Peak mean serum creatinine levels +/- standard errors in Groups 1 through 4 were 12.6 +/- 1.97, 7.8 +/- 0.90, 7.1 +/- 1.26, and 8.2 +/- 1.09, respectively. Repeated measures analysis of variance showed statistically significant differences between the groups with respect to their serum creatinine profiles (Wald's test x2 with 3 df = 22.39, P value less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Evidence for the participation of activated oxygen species and the resulting peroxidation of lipids in the killing of cultured hepatocytes by aryl halides.

Primary cultures of rat hepatocytes were used to explore the mechanisms of the toxicity of aryl halides. The sensitivity of the hepatocytes to chloro-, bromo-, and iodobenzene was enhanced by inhibition of glutathione reductase with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In each case, the increased cell killing depended on the metabolism of the toxicant, a result shown by the protective effect of SKF-525A, an inhibitor of mixed function oxidation. BCNU decreased the metabolism of [14C]bromobenzene and the covalent binding of its metabolites by 20%. Chelation by deferoxamine of a cellular source of ferric iron prevented the cell killing in the presence or absence of BCNU. Deferoxamine had no effect on the metabolism or the covalent binding of [14C]bromobenzene. Similarly, the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD) reduced the cell killing and had no effect on the metabolism of [14C]bromobenzene. Thus, the toxicity of the three aryl halides was manipulated in ways that modify the sensitivity of hepatocytes to an oxidative stress, and the changes in cell killing occurred without parallel changes in the metabolism of [14C]bromobenzene or the covalent binding of its metabolites.

Animals↗
PubMed1990

Trypanosoma cruzi receptors for human transferrin and their role.

Trypanosoma cruzi amastigotes present receptors for human transferrin as indicated by the saturable binding of 125I-transferrin to this form of the parasite. Computerized Scatchard analysis revealed one class of receptors present at 8.1 X 10(4) receptors per amastigote with a Kd of 2.82 microM. Immunofluorescence studies indicate that more than 90% of amastigotes bind human transferrin, whereas trypomastigotes do not. Iron is required for amastigote growth in cell-free medium since deferoxamine, an iron chelator, inhibits amastigote growth. Amastigote growth is restored when deferoxamine is removed from the medium. 59Fe-transferrin, which bound to amastigotes at 4 degrees C for 1 h, was readily dissociated from the parasite surface upon treatment with acid. However, this treatment did not disrupt binding that occurred at 37 degrees C for 1 h. Amastigote growth in cell-free medium is inhibited in ferrotransferrin-depleted serum, and addition of ferrotransferrin but not apotransferrin restores parasite growth. Western blots of solubilized amastigote membranes probed with anti-human transferrin receptor antibody recognize a protein of 200 kDa. This protein is present on the amastigote cell surface; therefore, human transferrin seems to interact with a 200-kDa surface amastigote protein receptor. Iron, which is essential for amastigote growth, thus appears to be delivered to T. cruzi amastigotes by transferrin receptor-mediated endocytosis.

Animals↗
PubMed1991

Evidence for an early free radical-mediated reperfusion injury in frostbite.

Frostbite is characterized by acute tissue injury induced by freezing and thawing. Initial complete ischemia is followed by reperfusion and later, tissue necrosis. These vascular events support the hypothesis that free radical-mediated reperfusion injury at thawing might contribute to tissue necrosis after frostbite in a manner similar to that seen after normothermic ischemia. To test this hypothesis, rabbit ears were frozen at -21 degrees C for 30, 60, 90, or 120 s and rewarmed at room temperature (22 degrees C). Rabbits were treated "blindly" with saline alone, highly purified, pharmaceutical grade superoxide dismutase (SOD), allopurinol, or deferoxamine. The area of ear necrosis was determined 3 weeks after frostbite by "blinded" morphometry. The administration of SOD at the time of thawing significantly improved viability in ears frozen for 60 and 90 s, but not in those frozen for 30 or 120 s. Deferoxamine also improved viability in ears frozen for 60 s. Allopurinol did not significantly affect ear survival. Electron micrographs showed the appearance of severe endothelial cell injury beginning during freezing and extending through early reperfusion. Later, neutrophil adhesion, erythrocyte aggregation, and microvascular stasis were seen. These findings suggest that free radical-mediated reperfusion injury has a role in frostbite, and quantitate the proportion of the injury that is due to this mechanism.

Allopurinol↗
PubMed1994

Extracellular iron chelators protect kidney cells from hypoxia/reoxygenation.

Iron is an important contributor to reoxygenation injury because of its ability to promote hydroxyl radical formation. In previous in vivo studies, we demonstrated that iron chelators that underwent glomerular filtration provided significant protection against postischemic renal injury. An in vitro system was employed to further characterize the protection provided by extracellular iron chelators. Primary cultures of rat proximal tubular epithelial cells were subjected to 60 min hypoxia and 30 min reoxygenation (H/R). During H/R, there was a 67% increase in ferrozine-detectable iron in cell homogenates and increased release of iron into the extracellular space. Cells pretreated with either deferoxamine (DFO) or hydroxyethyl starch-conjugated deferoxamine (HES-DFO), an iron chelator predicted to be confined to the extracellular space, were greatly protected against lethal cell injury. To further localize the site of action of DFO and HES-DFO, tracer quantities of 59Fe were added to DFO or HES-DFO, and their distribution after 2 h was quantitated. Less than 0.1% of DFO entered the cells, whereas essentially none of the HES-DFO was cell-associated. These findings suggest that iron was released during hypoxia/reoxygenation and caused lethal cell injury. Iron chelators confined to the extracellular space provided substantial protection against injury.

Animals↗
PubMed1994

The increased susceptibility to hydrogen peroxide of the (post-)ischemic rat heart is associated with the magnitude of the low molecular weight iron pool.

Recently we have shown that intracellular low molecular weight (LMW) iron increases during ischemia. It is hypothesized that this increase in LMW iron during ischemia underlies the reported hydrogen peroxide toxicity toward ischemic hearts. To investigate this hypothesis, rat hearts were subjected to 15 min of no-flow ischemia and reperfused with buffer saturated against 95% N2 and 5% CO2 (anoxic reperfusion) for 7 min. Hearts were then switched to buffer saturated against 95% O2 and 5% CO2 (reoxygenation) to assess functional recovery. The cardiac function recovered to 80 +/- 7% of the preischemic value. When the anoxic reperfusion was applied in the presence of 10 microM hydrogen peroxide, functional recovery after reoxygenation was 47 +/- 7%. Hearts that were perfused with deferoxamine before ischemia and then subjected to ischemia and anoxic reperfusion in the presence of 10 microM hydrogen peroxide recovered to 78 +/- 8%. Immediate reoxygenation after ischemia led to only 45 +/- 6% recovery of function. During ischemia, LMW iron increased from 49 +/- 45 to 183 +/- 45 pmol/mg protein (p < .05) and decreased to 58 +/- 38 pmol/mg protein (p < .05) during the subsequent anoxic perfusion. Rat hearts preloaded with deferoxamine showed a slightly higher LMW iron content than normal (85 +/- 23 and 49 +/- 45 pmol/mg protein, respectively; n.s.), which showed a small, nonsignificant increase up to 136 +/- 42 pmol/mg protein after 15 min of ischemia. No significant changes were found in reduced and oxidized glutathione content and glutathione peroxidase or catalase activities under those conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Significance of fructose-induced protein oxidation and formation of advanced glycation end product.

To investigate the significance of fructose-induced protein modification, we examined both fructose- and glucose-induced protein oxidation and the formation of advanced glycation end products (AGE) in vitro. Albumin incubated in the presence of 100 mM fructose at 37 degrees C for 1 week showed 5.1-fold and 3.1-fold increases in the content of carbonyl, which is a marker for oxidized protein, when compared with either control incubated without sugar or with 100 mM glucose. Similarly, the same incubation with fructose increased the fluorescence intensity over 100-fold and 15-fold formation compared with that of no sugar and glucose controls, respectively. Both fructose-induced fluorescence and protein oxidation were almost completely suppressed in the presence of the iron chelator; deferoxamine (100 microM), the hydroxyl radical scavenger; MK-447 (1 mM), or aminoguanidine (200 mM), which is an inhibitor of AGE formation. In contrast, the fructose-induced formation of fluorescent albumin was potentiated in the presence of 100 microM FeCl2. This was completely inhibited in the presence of 60 microM or more deferoxamine. These results suggest that fructose promotes both AGE formation and protein oxidation possibly through the formation of hydroxyl radicals.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Perinatal asphyxia, hyperthermia and hyperferremia as factors inducing behavioural disturbances in adulthood: a rat model.

Alertness was studied in adult male Wistar rats after neonatal critical anoxia applied under three different thermal conditions: (i) at physiological neonatal body temperature of 33 degrees C, (ii) at body temperature elevated to 37 degrees C, and (iii) at body temperature elevated to 39 degrees C (both during anoxia and for 2 h postanoxia). To elucidate the effect of iron-dependent postanoxic oxidative damage to the brain, half of the group (iii) was injected with deferoxamine, a chelator of iron. Postanoxic behavioural disturbances were recorded in open-field, elevated plus-maze, and sudden silence tests when the rats reached the age of 4 month. Moreover, spontaneous motor activity of the rats was recorded radiotelemetrically in their home-cages. Both open-field stress-induced and spontaneous motor activity were reduced in rats subjected to neonatal anoxia under hyperthermic conditions. In contrast, these rats were hyperactive in the plus-maze test. Both the plus-maze and sudden silence tests revealed that these rats show reduced alertness to external stimuli signalling potential dangers. The behavioural disturbances were prevented by the body temperature of 33 degrees C and by postanoxic administration of deferoxamine. These data support the conclusion that permanent postanoxic behavioural disturbances are due to iron-dependent oxidative damage to the brain, which can be prevented by the reduced neonatal body temperature.

Analysis of Variance↗
PubMed2004

Effect on ribonucleotide reductase of novel lipophilic iron chelators: the desferri-exochelins.

Desferri-exochelins are siderophores secreted by Mycobacterium tuberculosis that are both lipid- and water-soluble and have a high binding affinity for iron. Desferri-exochelin 772SM inhibits DNA replication and ribonucleotide reductase activity at 10-fold less concentration than the lipid-insoluble iron chelator deferoxamine, which is currently in clinical use. Neither chelator can extract iron directly from ribonucleotide reductase. However, because of its lipid-solubility and high binding affinity, desferri-exochelin is able to enter cells rapidly and access intracellular iron, while deferoxamine has limited capacity to cross the cell membrane.

Breast Neoplasms↗
PubMed2005

Effect of neonatal body temperature on postanoxic, potentially neurotoxic iron accumulation in the rat brain.

In asphyxiated newborns iron, released from heme and ferritin and deposited in the brain, contributes to neurodegeneration. Because hypothermia provides neuroprotection, newborn mammals, showing spontaneously reduced body temperature, might avoid the iron-mediated neurotoxicity. Therefore, we decided to study the effects of body temperature and chelation of iron with deferoxamine on iron accumulation in the brain of three weeks old rats exposed neonatally to a critical anoxia. At the age of two days, newborn rats were exposed to anoxia in 100% nitrogen atmosphere. Rectal temperature was kept at 33 degrees C (typical of the rat neonates), or elevated to a level typical of febrile (39 degrees C) adults. Control rats were exposed to atmospheric air in the respective thermal conditions. Half of the rats exposed to anoxia under hyperthermic conditions were injected with deferoxamine (DF), immediately after anoxia and 24 h later. Regional changes in cerebral iron deposition were examined in the frontal cortex, the hippocampus and the striatum, using iron histochemistry, when the rats reached the age of three weeks. Increased iron staining was found in neurons of each of the three cerebral regions in rats exposed to neonatal anoxia under hyperthermic conditions and the iron accumulation was prevented by postanoxic DF injection. In conclusion, febrile body temperature amplifies cerebral hyperferremia, which might induce neurodegenerative disturbances in the brain. On the other hand, a protection against the brain hyperferremia can be achieved by both the reduced physiological neonatal body temperature and by postasphyxic DF administration.

3,3'-Diaminobenzidine↗
PubMed2003

Performance characteristics of the Dimension RxL iron and total iron-binding capacity methods.

BACKGROUND: Measurements of serum iron and total iron-binding capacity (TIBC) can be used to aid the diagnosis of iron deficiency and iron overload states. A variety of different methods for these measurements are commercially available. METHODS: Linearity, imprecision and hemoglobin interference of homogeneous iron and TIBC methods on a Dimension RxL analyzer were assessed. Method comparison studies were performed with a Vitros 950 analyzer. RESULTS: The Dimension RxL iron method was linear from 40 to 1000 microg/dl. The coefficient of variation of the iron and TIBC methods were <4% and <2%, respectively, at iron concentrations of 68 and 228 microg/dl and TIBC concentrations of 206 and 384 microg/dl. Comparison of the Vitros 950 and Dimension RxL iron methods gave a slope of 0.97, an intercept of 6.0 and r=0.99. Corresponding results for the TIBC methods were 1.02, -6.6 and r=0.97, respectively. Simulation of acute iron overload in vitro did not produce the same effect on TIBC measurements as in vivo overload. Iron recovery by the Dimension RxL method was reduced 40-60% by the addition of deferoxamine at a concentration of 200 micromol/l. CONCLUSIONS: The Dimension RxL assay provides acceptable measurements of iron and TIBC in routine patient samples. Iron measurements are unreliable in the presence of deferoxamine.

Anemia, Iron-Deficiency↗
PubMed1997

Analysis and assessment of the capacity of neutrophils to produce reactive oxygen species in a 96-well microplate format using lucigenin- and luminol-dependent chemiluminescence.

The chemiluminescence (CL) assay has been used to measure the reactive oxygen species (ROS)-generating capacity of phagocytes. To achieve more optimal measurement conditions for a multi-channel microplate photon-counting CL analyzer with the cooled charge-coupled device (CCD) camera which offers enhanced sensitivity, we investigated factors affecting the variability in lucigenin-dependent CL (LgCL) measurement of human neutrophils stimulated with either opsonized zymosan (OZ) or phorbol myristate acetate (PMA). We obtained sensitive LgCL responses with good reproducibility and rapid data-acquisition using 50 microl neutrophils (3 X 10(6) cells/ml) and 50 microl of 0.5 mM lucigenin per well, in addition to either 100 microl of OZ (5 mg/ml) when zymosan was opsonized with 10-20% serum or 100 microl of PMA solution (1 X 10(-6) M) with automatic regular intervals of mixing and detection during the continuous measurement at 37 degrees C. Furthermore, we studied the contribution of various ROS to LgCL and luminol-dependent CL (LmCL) using modulators of ROS metabolism including superoxide dismutase (SOD), catalase, deferoxamine and sodium azide (NaN3). LgCL was inhibited by SOD but not by the other agents, whereas LmCL was inhibited by NaN3 and deferoxamine. Thus, it was demonstrated that LgCL detects the superoxide anion with high selectivity whereas the LmCL assay measures myeloperoxidase (MPO)-mediated formation of hypochlorous acid. Such microplate-based multiple measurements facilitate the accurate assessment of phagocytic function.

Acridines↗
PubMed1990

Prospective evaluation of aluminum loading from formula in infants with uremia.

Assessment of potential aluminum loading from regular ingestion of a commercial infant formula (Similac PM 60/40), as the only milk substitute, was made in 14 infants aged 9.6 +/- 4.4 months who were also undergoing continuous cycling peritoneal dialysis. Tissue aluminum accumulation was assessed by serial measurements of plasma aluminum levels, from the increment in plasma aluminum after a standardized deferoxamine infusion, and from quantitative histomorphometry of bone and measurements of total bone aluminum content. Initial mean plasma aluminum levels were 0.61 +/- 0.32 mumol/L, (normal 0.30 +/- 0.04 mumol/L), and values were less than 0.92 mumol/L during the follow-up of 20 +/- 8 months. Plasma aluminum levels increased from 0.59 +/- 0.18 to 0.88 +/- 0.22 mumol/L after a single dose of deferoxamine. The histochemical stain for bone aluminum was negative for all patients, and the bone aluminum content was 0.27 +/- 0.22 mmol/kg dry weight (normal 0.08 +/- 0.04 mmol/kg dry weight). Thus the infant formula Similac PM 60/40 can be safely used in infants with chronic renal failure.

Aluminum↗
PubMed1997

Pharmacologic inhibition of transglutaminase-induced cross-linking of Alzheimer's amyloid beta-peptide.

The brain of Alzheimer's disease (AD) patients contains deposits of amyloid beta-peptide (A beta). Recent studies have shown that A beta is a substrate for tissue transglutaminase (TGase), which induces the formation of cross-linked dimers and polymers, and that tacrine, indomethacin and deferoxamine, which have widely different chemical structures, attenuate the progression of symptoms of AD. This report evaluated the potential of a total of ten different pharmacological agents to inhibit TGase-induced cross-linking of A beta, including known TGase inhibitors (dansylcadaverine, spermine), non-steroidal anti-inflammatory drugs (indomethacin, meclofenamic acid, diflunisal, salicylic acid), monoamine oxidase inhibitors (tranylcypromine, phenelzine), an acetylcholinesterase inhibitor (tacrine), and an iron chelating agent (deferoxamine). All but one (salicylic acid) of these ten agents had an inhibitory effect on TGase-induced A beta cross-linking. These results suggest that inhibition of TGase-induced cross-linking of A beta is a potential pharmacologic target for the treatment of AD. A method is also presented for the determination of percent inhibition of TGase-induced A beta cross-linking based on the separated monomer, dimer and polymer bands on SDS-PAGE gels.

Amyloid beta-Peptides↗
PubMed1986

Iron poisoning.

Iron poisoning continues to be a major toxicologic problem, with major impact on the gastrointestinal and circulatory systems. Failure to recognize the severity of iron intoxication may result in an inappropriate level of intervention. By using estimates of the total body burden of iron, clinical symptoms, and the serum iron concentration, an appropriate decision can be made to initiate aggressive chelation therapy with deferoxamine. In severe intoxication, the use of intravenous deferoxamine is indicated, along with supportive care, with particular attention to maintaining the intravascular volume. Other important measures include correction of acidosis and disorders of coagulation and replacement of blood components when there is evidence of gastrointestinal hemorrhage. Under rare circumstances in which large numbers of iron tablets are present in the gastrointestinal tract, surgical removal may be indicated. In addition, measures such as hemodialysis and exchange transfusion should be reserved for those unusual poisonings in which more conservative therapy is unsuccessful. In rare cases of iron intoxication, late sequelae such as hepatic necrosis and gastrointestinal scarring with obstruction may occur. The prompt recognition and initiation of management of children with acute iron poisoning is the single most critical element in decreasing the morbidity and mortality associated with these products.

Absorption↗
PubMed2003

Oxalate deposition on asbestos bodies.

We report on a deposition of oxalate crystals on ferruginous bodies after occupational exposure to asbestos demonstrated in 3 patients. We investigated the mechanism and possible significance of this deposition by testing the hypothesis that oxalate generated through nonenzymatic oxidation of ascorbate by asbestos-associated iron accounts for the deposition of the crystal on a ferruginous body. Crocidolite asbestos (1000 microg/mL) was incubated with 500 micromol H(2)O(2) and 500 micromol ascorbate for 24 hours at 22 degrees C. The dependence of oxalate generation on iron-catalyzed oxidant production was tested with the both the metal chelator deferoxamine and the radical scavenger dimethylthiourea. Incubation of crocidolite, H(2)O(2), and ascorbate in vitro generated approximately 42 nmol of oxalate in 24 hours. Oxalate generation was diminished significantly by the inclusion of either deferoxamine or dimethylthiourea in the reaction mixture. Incubation of asbestos bodies and uncoated fibers isolated from human lung with 500 micromol H(2)O(2) and 500 micromol ascorbate for 24 hours at 22 degrees C resulted in the generation of numerous oxalate crystals. We conclude that iron-catalyzed production of oxalate from ascorbate can account for the deposition of this crystal on ferruginous bodies.

Asbestos, Crocidolite↗