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PubMedDate not supplied

Induction of apoptosis by iron depletion in the human breast cancer MCF-7 cell line and the 13762NF rat mammary adenocarcinoma in vivo.

It is known that the interruption of normal iron metabolism with chelators of iron, toxic metals, toxic metals bound to transferrin, or anti-transferrin receptor antibodies leads to significant inhibition of tumor cell growth in cell culture systems and animal models. In the present study, we found that iron depletion was produced by the iron chelator deferoxamine mesylate, the free toxic metals gallium or indium, and the toxic metals gallium or indium bound to transferrin in the MCF-7 human breast cancer cell line, and this induced the condensation and fragmentation of chromatin, and the formation of DNA fragments characteristic of apoptosis. The induction of apoptosis was quantitated with acridine orange and ethidium bromide staining of apoptotic cells, separation of fragmented DNA from radiolabeled cells, and in situ terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assays. The apoptosis, caused by deferoxamine mesylate, and gallium or indium bound to transferrin in the MCF-7 cells, can be completely inhibited by excess ferric chloride or equimolar iron-loaded transferrin. Gallium-transferrin and indium-transferrin complexes induced more apoptosis than their respective salts in the MCF-7 cells. Deferoxamine mesylate induced a small increase in the endogenous expression of both the bcl-2 and bax genes in the MCF-7 cells and this can be prevented by ferric chloride. In the 13762NF rat mammary adenocarcinoma model, in situ TUNEL assays showed that the iron-deficiency following a low iron diet or intravenous injection of deferoxamine mesylate produced 5.32 +/- 3.90% and 6.46 +/- 3.58% of apoptotic cells, respectively, compared to 2.01 +/- 1.20% of apoptotic cells in the control rats maintained on a normal diet (p < 0.05 and p < 0.01, respectively, Student's t-test). This is the first report of iron depletion caused by a low iron diet or deferoxamine mesylate treatment inducing apoptosis in rats bearing the 13762NF marnmary adenocarcinoma.

Adenocarcinoma↗
PubMed1985

Ferric iron and superoxide ions are required for the killing of cultured hepatocytes by hydrogen peroxide. Evidence for the participation of hydroxyl radicals formed by an iron-catalyzed Haber-Weiss reaction.

Cultured hepatocytes pretreated with the ferric iron chelator deferoxamine were resistant to the toxicity of H2O2 generated by either glucose oxidase or by the metabolism of menadione (2-methyl-1,4-naphthoquinone). Ferric, ferrous, or cupric ions restored the sensitivity of the cells to H2O2. Deferoxamine added to hepatocytes previously treated with this chelator prevented the restoration of cell killing by only ferric iron. The free radical scavengers mannitol, thiourea, benzoate, and 4-methylmercapto-2-oxobutyrate protected either native cells exposed to H2O2 or pretreated hepatocytes exposed to H2O2 and given ferric or ferrous iron. Superoxide dismutase prevented the killing of native hepatocytes by either glucose oxidase or menadione. With deferoxamine-pretreated hepatocytes, superoxide dismutase prevented the cell killing dependent upon the addition of ferric but not ferrous iron. Catalase prevented the killing by menadione of deferoxamine-pretreated hepatocytes given either ferric or ferrous iron. Deferoxamine pretreatment did not prevent the toxicity of t-butyl hydroperoxide but did, however, prevent that of cumene hydroperoxide. It is concluded that both ferric iron and superoxide ions are required for the killing of cultured hepatocytes by H2O2. The toxicity of H2O2 is also dependent upon its reaction with ferrous iron to form hydroxyl radicals by the Fenton reaction. The ferrous iron needed for this reaction is formed by the reduction of cellular ferric iron by superoxide ions. Such a sequence corresponds to the so-called iron-catalyzed Haber-Weiss reaction, and the present report documents its participation in the killing of intact hepatocytes by H2O2. Cumene hydroperoxide but not t-butyl hydroperoxide closely models the toxicity of hydrogen peroxide.

Animals↗
PubMed1988

[A new concept of cardioplegic protection in cardiac surgery: iron chelation].

Hydroxyl is one of the most cytotoxic of all oxygen-derived free radicals produced during the myocardial ischaemia-reperfusion sequence. The purpose of the present study was to determine the effects of various interventions aimed at diminishing the production of hydroxyl radicals by reducing either one of their precursors (hydrogen peroxide) or the metal (ferric iron) which catalyzes the reaction generating these radicals. Sixty isolated and perfused rat hearts with isovolaemic contraction were studied. Except for non-ischaemic controls, these hearts were subjected to a 3-hour cardioplegic arrest in hypothermia (15-18 degrees C) followed by a 45-min reperfusion. The following interventions were performed: pretreatment with peroxidase, a hydrogen peroxide scavenger; pretreatment with peroxidase combined with deferoxamine, an ironchelating agent; pretreatment with peroxidase followed by addition of deferoxamine to the cardioplegic solution; addition of deferoxamine to the cardioplegic solution without pretreatment with the enzyme. Judging from the post-ischaemic values of developed pressure (maximum systolic pressure--diastolic pressure), left ventricular dP/dt and diastolic pressure and coronary flow rate, it appeared that the best myocardial protection was provided by deferoxamine-enriched cardioplegia. This study confirms that hydroxyl radicals most probably play a role in the genesis of the myocardial lesions associated with global ischaemia followed by reperfusion. Moreover, our results highlight the potential value of deferoxamine added to cardioplegic protection in heart surgery performed under extracorporeal circulation.

Animals↗
PubMed1993

Cold-induced brain edema in mice. Involvement of extracellular superoxide dismutase and nitric oxide.

The role of extracellular superoxide in the pathogenesis of vasogenic edema was studied using transgenic mice expressing a 5-fold increase in extracellular superoxide dismutase (EC-SOD) activity in their brains. Increased EC-SOD expression offered significant protection against edema development after cold-induced injury (44% less edema than nontransgenic littermates, p < 0.05). Since iron may contribute to vasogenic edema by catalyzing the production of hydroxyl radical from superoxide and hydrogen peroxide, the effects of the chelator deferoxamine were studied. Deferoxamine reduced edema formation after cold-induced injury (43% less edema than controls, p < 0.05); however, treatment with iron-saturated deferoxamine also reduced edema development in mice (32-48% less edema, p < 0.05). This suggested that the protection offered by deferoxamine was independent of its ability to chelate iron. An iron-independent mechanism by which superoxide can contribute to vasogenic edema is via reaction with nitric oxide to produce the potentially toxic peroxynitrite anion, which is also scavenged by deferoxamine. Mice treated with an inhibitor of nitric oxide synthase were protected against cold-induced edema (37% less edema, p < 0.05). EC-SOD transgenic mice received no additional protection by inhibition of nitric oxide synthesis, supporting this novel alternative mechanism of edema formation.

Amino Acid Oxidoreductases↗
PubMed1994

The iron metabolism of the human neuroblastoma cell: lack of relationship between the efficacy of iron chelation and the inhibition of DNA synthesis.

The mechanisms of iron uptake from transferrin and the effects of iron chelators on these processes were investigated in human neuroblastoma cells. This study was performed because numerous reports have indicated that neuroblastoma cells contain iron-rich ferritin and are also especially sensitive to iron chelation by deferoxamine. The mechanisms of iron and transferrin uptake were examined in the human neuroblastoma cell line SK-N-MC by using human transferrin labeled with iodine 125 and iron 59. Internalized and membrane-bound 59Fe and 125I-transferrin were separated with the protease pronase. Total internalized and membrane 125I-transferrin uptake was biphasic with time, whereas total and internalized 59Fe uptake was linear. Iron uptake from transferrin was prevented by incubation at 4 degrees C and also by lysosomotrophic agents. In addition, 59Fe uptake occurred by two processes. The first process was consistent with receptor-mediated endocytosis involving internalization of transferrin bound to specific binding sites. Iron uptake also occurred by a second process, which was not saturable up to a transferrin concentration of 0.06 mg/ml. In terms of quantitative iron uptake, however, the second process was far less important than receptor-mediated endocytosis. Deferoxamine (0.25 mmol/L) only slightly increased 59Fe release from prelabeled cells; the orally effective iron chelator pyridoxal isonicotinoyl hydrazone (0.25 mmol/L) was six times more effective. Moreover, when pyridoxal isonicotinoyl hydrazone (0.2 mmol/L) was added together with labeled transferrin over a 2-hour incubation, 59Fe uptake from transferrin decreased to 18% of the control value, whereas deferoxamine (0.2 mmol/L) had no appreciable effect. Even though deferoxamine (0.1 mmol/L) had little effect on 59Fe uptake or release, it reduced uptake of tritiated thymidine to 33% of the control value after a 24-hour incubation. Three analogs of pyridoxal isonicotinoyl hydrazone, pyridoxal benzoyl hydrazone (#101), pyridoxal p-methoxybenzoyl hydrazone (#107), and pyridoxal m-fluorobenzoyl hydrazone (#109), had chelation activities comparable to that of pyridoxal isonicotinoyl hydrazone and were more effective than either deferoxamine or pyridoxal isonicotinoyl hydrazone at preventing tritiated thymidine uptake. These results suggest that the pyridoxal isonicotinoyl hydrazone analogs have potential as effective antiproliferative agents and deserve further investigation.

DNA↗
PubMed1994

Desferal attenuates TNF release following hepatic ischemia/reperfusion.

Iron chelators have been shown to protect against oxygen free radical injury occurring in association with ischemia/reperfusion (I/R). Tumor necrosis factor alpha (TNF) represents a major mediator of the pulmonary and hepatic injury occurring after hepatic I/R since pretreatment with anti-TNF antibody results in significant protection against both the lung and liver injury following this insult. We were therefore interested in the possible association of the protective actions of deferoxamine (Desferal) following hepatic I/R and subsequent TNF release. A rat model of hepatic I/R was used to evaluate this; four experimental groups were studied. Animals in I/R underwent 90 min of hepatic ischemia with subsequent reperfusion. DES-I/R animals were pretreated with 200 mg of deferoxamine and VEH-I/R rats were given an equivalent amount of vehicle prior to hepatic I/R. SHAM animals underwent sham laparotomy alone. Plasma specimens were obtained and analyzed for TNF using a cytolytic bioassay based on the WEHI 164 subclone 13 cell line. Mean peak TNF levels following deferoxamine pretreatment was 110.38 +/- 24.68 pg/ml, as compared to mean peak TNF levels of 213.64 +/- 38.09 pg/ml in the VEH-I/R group (P < 0.01). Lung injury following hepatic I/R was evaluated by assessment of pulmonary microvascular permeability and by evaluation of pulmonary neutrophil infiltration as measured by pulmonary myeloperoxidase (MPO) content. Pretreatment with deferoxamine resulted in a significant decrease in lung leak as compared to animals pretreated with vehicle prior to I/R (DES-I/R = 0.192 +/- 0.013, VEH-I/R = 0.690 +/- 0.050; P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1994

Proposed toxic oxidant inhibitors fail to reduce brain edema.

Toxic oxidants (oxygen free radicals) have been implicated in the formation of brain edema from ischemia-reperfusion injury or tumor growth. We investigated the ability of an iron chelator, a calcium channel blocker, and a xanthine oxidase inhibitor to reduce formation of brain edema following a cold lesion in cats. The agents were given independently of each other in an attempt to inhibit the Haber-Weiss reaction, prevent Ca++ modulated uncoupling of oxidative phosphorylation, and inhibit the generation of toxic oxidants via xanthine oxidase, respectively. Pentastarch-deferoxamine conjugate at a dose of 50 mg/kg was given 15 minutes before and 60 minutes after the cold lesion. Nimodipine was given at a dose of 1 mg/kg 1 hour before and 2 hours after the cold lesion. Allopurinol was given at a dose of 50 mg/kg 24 hours before, at the time of the lesion and, 24 and 48 hours after the lesion. Gravimetric measurements of multiple brain areas were performed at 24 hours post-lesion in the pentastarch-deferoxamine and nimodipine groups and at 72 hours post-lesion in the allopurinol group. None of these agents led to significant reduction in brain edema formation as measured with a gravimetric column of kerosene and bromobenzene. Pentastarch-deferoxamine conjugate was utilized to avoid the confounding effects of arterial hypotension which is seen with intravenous deferoxamine. There was even a suggestion of increased edema in the periventricular white matter in animals treated with nimodipine. Taken together, independent inhibition of the Haber-Weiss reaction, of calcium channels, or of xanthine oxidase does not reduce formation of brain edema in the cold lesion model.

Allopurinol↗
PubMedDate not supplied

Non-insulin-dependent diabetes mellitus and elevated serum ferritin level.

An elevated serum ferritin concentration recently has been shown to be associated with coronary artery disease and its risk factors, including blood glucose concentration. The purpose of this study is to establish the prevalence of elevated levels of serum ferritin in patients with non-insulin-dependent diabetes mellitus (NIDDM) without hemochromatosis and to determine whether or not deferoxamine is of therapeutic value in treating such patients. The level of serum ferritin was measured in consecutive eligible patients with NIDDM seen at routine outpatient visits. Five patients with an elevated serum ferritin were treated with deferoxamine, 1 g intramuscularly, twice a week for 12 weeks. The level of serum ferritin was measured every 4 weeks, and the level of glycosylated hemoglobin was measured at baseline, at the end of the treatment, and 12 weeks after treatment was completed. The level of serum ferritin was elevated in 34 of 102 (33%) patients with NIDDM. The level of serum ferritin remained elevated in 30 of 32 (94%) of these patients on repeat testing. In three of the five patients treated with deferoxamine, the level of serum ferritin was normalized, but no patient had an appreciable change in dosage of medication for diabetes or glycemic control. Non-insulin-dependent diabetes is a condition frequently associated with elevated levels of serum ferritin. Treatment with deferoxamine intramuscularly was not effective in improving control of glucose in our patient group.

Aged↗
PubMed2003

Ageing exacerbates the cardiotoxicity of hydrogen peroxide through the Fenton reaction in rats.

Reactive oxygen species (ROS) are involved in the post-ischemic reperfusion syndrome of the myocardium. Moreover, ageing is associated with an increased cardiac sensitivity to both ischemia and reperfusion. The aim of the present study was to determine whether the lower tolerance of aged hearts to reperfusion could be due to an increased sensitivity to the ROS that are produced during the early phase of reperfusion. For this purpose isolated perfused hearts from adult (4 months) and aged (24 months) rats were perfused with a buffer containing 150 microM of hydrogen peroxide (H(2)O(2)) in presence or absence of deferoxamine mesylate (150 microM), an iron chelator. H(2)O(2) perfusion was continued until left ventricular developed pressure had decreased up to 20% of its initial value. Ageing led to a significant reduction of the duration of the H(2)O(2) perfusion required for inducing a 80% functional alteration. Although deferoxamine did not affect this parameter in adult rats, it significantly increased the duration of H(2)O(2)-perfusion in senescent hearts (control: 14.0+/-0.9 min vs. deferoxamine: 18.1+/-1.0, P<0.05). Similarly, ageing aggravated cardiac contracture induced by H(2)O(2)-perfusion. Again, deferoxamine, which had no effect on this parameter in young adult hearts, significantly reduced the contracture of senescent rat hearts. To conclude, our data clearly show that ageing is associated with an increased sensitivity of the myocardium to hydrogen peroxide, which is partly reversed by iron chelation. These results suggest that the iron-catalyzed Fenton reaction producing hydroxyl radicals might be greater in hearts from senescent rats than in hearts from young adults.

Aging↗
PubMed1987

Microcytic anemia in dialysis patients: reversible marker of aluminum toxicity.

Improvement of microcytic anemia after deferoxamine treatment is described in eight long-term dialysis patients with high serum aluminum concentration and other clinical signs of aluminum toxicity. Hematocrit increase of 3 to 19 vol% was associated with correction of microcytosis, significant reduction in abnormal levels of free erythrocyte protoporphyrins, and amelioration of the bone-related symptoms and neurologic signs of aluminum intoxication. Increase in hematocrit, reversal of microcytosis, and reduction in protoporphyrin levels all correlated with the aluminum burden as indicated by the pretreatment serum aluminum levels and by the peak serum aluminum levels during mobilization with deferoxamine. Furthermore, deferoxamine resulted in marked improvement in anemia despite significant reduction in serum ferritin levels. This reversal of microcytosis with deferoxamine provides objective evidence verifying the toxicity of aluminum, and suggests that microcytosis may be an easily detected marker for both clinical diagnosis as well as response to treatment in some cases of aluminum intoxication.

Adult↗
PubMed2000

Intentional iron overdose in pregnancy--management and outcome.

The objectives of our study were to 1) determine if peak maternal serum iron level or toxicity stage after intentional overdose is associated with adverse maternal-fetal outcome, and 2) describe the use of deferoxamine antidote therapy in obstetric patients. A computer search of the English language literature from 1966-1998 used the key words iron toxicity, iron poisoning, deferoxamine, and pregnancy to identify peer-reviewed papers reporting intentional iron overdoses in pregnancy. Two investigators independently extracted data from articles and their references including stage of toxicity (0 = asymptomatic, 1 = gastrointestinal symptoms, 2 = metabolic disturbance, 3 = organ failure), with differences resolved by consensus. Statistical analysis used the Student t-test, Fisher exact test, or ANOVA, as appropriate. Fourteen publications were identified, describing 61 cases of obstetric iron overdose, including one recent case at our institution. Compared with women who had lower peak levels, women with peak serum iron levels > or =400 mcg/dL were more frequently symptomatic (12/13 vs. 5/10, respectively, p = 0.05). Peak iron level > or =400 mcg/dL was not associated with increased risk of spontaneous abortion, preterm delivery, congenital anomalies, or maternal death. However, patients with stage 3 toxicity were more likely to spontaneously abort (1/3 vs. 1/56, respectively), deliver preterm (2/3 vs. 6/56, respectively), or experience maternal death (3/3 vs. 0/56, respectively). The proportions of patients treated with deferoxamine and total dosages of deferoxamine were similar by peak iron level (> or =400 vs. <400 mcg/dL) and toxicity stage (0-3). Peak iron levels > or =400 mcg/dL are associated with symptomatic iron overdose. Stage 3 toxicity is associated with spontaneous abortion, preterm delivery, and maternal death.

Adolescent↗
PubMed1998

Effects of aluminum ions on K(+)-induced contraction in ileal longitudinal smooth muscle.

The mechanism of the inhibition of K(+)-induced contraction caused by aluminum ions (Al3+) was analyzed in ileal longitudinal muscle and taenia coli of guinea-pig. Al3+ (2-5 mM) inhibited dose-dependently the high-K+ (60 mM, hypertonic)-induced contraction in ileal muscle. Al3+ reduced the size of the maximal response to Ca2+ without shifting the concentration-response curves to Ca2+ in taenia coli. Al3+ caused a significant decrease in Ca uptake, measured by the lanthanum method, during the K(+)-induced ileal first phase of the response. Following treatment with 5 mM Al3+ for 0.5-20 min, the ileal K(+)-induced contraction returned to a greater extent, after washing with medium containing the chelator deferoxamine, compared to normal medium. However, with increasing duration, > 30 min of Al3+ treatment, the K(+)-induced contraction did not recover, despite washing with deferoxamine. The aluminum in the cells was even more eliminated by washing with deferoxamine when the duration of Al3+ treatment was < 20 min. The present findings indicate that the inhibitory action by Al3+ on K(+)-induced contraction at the shorter treatment (< 20 min) may result from the interference of calcium permeability at the cell membrane in ileal muscle. However, with increasing duration of Al3+ treatment, Al3+ ions accumulate in intracellular compartments where deferoxamine cannot reach, and it may exert an inhibitory action on internal sites in ileal cells.

Aluminum↗
PubMed1993

Failure of iron chelators to protect against cerebral infarction in hypoxia-ischemia.

In this study the ability of iron chelators to attenuate hypoxic-ischemic brain damage was assessed in hyperglycemic rats that were exposed to 1% carbon monoxide and right carotid occlusion. The animals received deferoxamine (50 mg/kg), manganese-deferoxamine (50 mg/kg) or vehicle i.p. 0.5 h prior to hypoxemic-ischemic exposure and at 0.5, 3 and 24 h post-exposure; with subsequent histological examination of the brain at 7 days recovery. The area of cerebral infarction was measured at three levels using video imaging methods. The mean percentage of total hemisphere that was infarcted in the three groups was: vehicle--28.5 +/- 5.0; deferoxamine--31.7 +/- 12.1; and manganese deferoxamine--30.6 +/- 6.8 (p-n.s.). The results as obtained in this preliminary study indicate that aggressive pre- and post-treatment with iron chelators has no ability to attenuate cerebral infarction in this model.

Animals↗
PubMed2003

Cardiac autonomic dysinnervation and myocardial blood flow in long-term Type 1 diabetic patients.

AIMS: The aim of the study was to assess scintigraphically the relationship between myocardial blood flow response and sympathetic dysinnervation in long-term Type 1 diabetic patients. Effects of the iron chelator deferoxamine on myocardial blood flow were studied and they were investigated according to the presence of cardiac sympathetic dysfunction. METHODS: Myocardial blood flow (MBF) was assessed with N-13 ammonia positron emission tomography in 13 long-term Type 1 diabetic patients and 13 control subjects at rest and in response to sympathetic stimulation (cold pressor test (CPT)). In diabetic patients, the study was repeated after preinfusion with deferoxamine. Furthermore, 123I metaiodobenzylguanidine (MIBG) scintigraphy was applied to assess regional cardiac sympathetic dysinnervation (uptake score 1 = normal, homogeneous uptake em leader 6 = no uptake). RESULTS: In diabetic patients, MBF increased in response to CPT from 78 +/- 18 ml/100 g/min to 84 +/- 26 ml/100 g (8%, P < 0.001). Control subjects demonstrated an increase from 63 +/- 17 ml/100 g to 84 +/- 26 ml/100 g (33%, P < 0.001), respectively. Resting MBF was higher in diabetic patients than in control subjects (P < 0.001). In diabetic patients, increase in MBF in response to CPT was significant in regions with a MIBG uptake score of 3 did not exhibit a significant increase in MBF in response to CPT. After administration of deferoxamine, the increase in MBF in response to CPT was 23% and the magnitude of increase was related to the MIBG uptake score (r = 0.40, P < 0.0001). CONCLUSIONS: Myocardial blood flow response to sympathetic stimulation is significantly impaired in long-term Type 1 diabetes. After preinfusion with deferoxamine the impairment is partially reversed and a relationship between myocardial blood flow and the extent of cardiac sympathetic dysfunction is observed.

3-Iodobenzylguanidine↗
PubMed1996

Limiting impairment of muscle function following ischemia and reperfusion in rabbits.

Reperfusion injury is a phenomenon complicating microvascular reconstruction. Extensive investigations of free-radical scavengers exist in the literature. The potential beneficial effects of verapamil, deferoxamine, and dimethylsulfoxide were studied in the rabbit forelimb subjected to 3 hr of tourniquet ischemia, followed by a period of reperfusion. Five minutes prior to tourniquet release, rabbits were given single intravenous infusions of normal saline, verapamil (0.2 mg/kg), deferoxamine (50 mg/kg), or dimethylsulfoxide (100 mg/kg). Following reperfusion, neither light microscopy nor laser Doppler flowmetry revealed significant differences between the sham and treated limbs. Muscle function was evaluated by measuring maximal twitch tensions in the flexor digitorum superficialis. Deterioration of muscle contractile function at 0.5, 3, and 24 hr after reperfusion was significantly improved by treatment with verapamil or deferoxamine. Conversely, dimethylsulfoxide worsened muscle function post ischemia. Dimethylsulfoxide does not appear to be beneficial, while verapamil and deferoxamine may be of benefit in mitigating reperfusion injury in microvascular transplantation.

Animals↗
PubMed2006

Severe infections in thalassaemic patients: prevalence and predisposing factors.

The incidence of infections among patients with thalassaemia and the role of risk factors for infection are uncertain. We studied the occurrence of infections necessitating hospitalisation in 92 homozygous beta-thalassaemia patients who had been followed longitudinally for decades, and investigated the role of potential risk factors for these infections. Pneumonia accounted for 26% of the infections and fever of unknown origin for 14%. Staphylococcus aureus was the major pathogen possibly related to injections associated with intensive chelation with deferoxamine. There was a significant increase in the rate of infection over time, notably after 15 years. Splenectomy correlated with the incidence of infection (P < 0.001) without being confounded by other variables and with highest frequencies of infections present after 10 years. A direct correlation between iron overload and infection was evident only before the initiation of iron-chelating treatment (P < 0.01). Following initiation of deferoxamine, paradoxically, the infection rate increased (P = 0.046). The combination of splenectomy and deferoxamine treatment was associated with the highest adjusted infection rate. Parathyroid dysfunction and glucose-6-phosphate dehydrogenase deficiency were significantly associated with infection (P = 0.02 and P = 0.04 respectively). The infection rate in thalassaemia is affected mainly by the duration of the disease and is increased by splenectomy and, in the long term, by treatment with deferoxamine.

Adolescent↗
PubMed1991

Role for iron in reactive oxygen species-mediated cytotoxicity to cultured rat gastric mucosal cells.

The gastric epithelium is exposed to oxygen species that are generated within the lumen. Reactive oxygen species, enzymatically generated, cause injury to cultured rat gastric mucosal cells. Much interest has been focused on the role of iron in producing oxidant-mediated injury to the gastric mucosa, because iron is a catalyst that promotes the production of .OH possibly from O2-. and H2O2 (Haber-Weiss reaction) or from H2O2 alone (Fenton reaction). With the use of an iron chelator and an iron binding protein, we examined the role of iron in producing oxidant-mediated injury to cultured gastric mucosal cells. Reactive oxygen species and H2O2 were generated by hypoxanthine-xanthine oxidase and glucose-glucose oxidase, respectively, in buffer without iron. Pretreatment with deferoxamine diminished hypoxanthine-xanthine oxidase-induced 51Cr release from prelabeled cells, dose dependently. Furthermore, addition of deferoxamine to the reactive oxygen species-generating system also protected against the injury. However, apotransferrin (which binds extracellular iron) failed to protect cells. Pretreatment with .OH scavengers was partially protective. Depletion of glutathione with diethyl maleate enhanced reactive oxygen species-mediated cytolysis; such cytolysis was inhibited by deferoxamine. Deferoxamine also decreased 51Cr release induced by glucose-glucose oxidase. We conclude that intracellular iron plays a crucial role in mediating oxygen radical damage to gastric mucosal cells. The .OH, produced from H2O2 by the iron-catalyzed Fenton reaction, seems to be the main mediator of oxidant-induced cytotoxicity to gastric mucosal cells in vitro.

Animals↗
PubMed1990

Role of iron on membrane phospholipid breakdown in ischemic-reperfused rat heart.

Oxygen-derived free radicals have been implicated in causing degradation of myocardial membrane phospholipids associated with ischemia and reperfusion. Since iron is known to catalyze the hydroxyl radical formation responsible for cellular injury, this study was designed to relate the role of iron with phospholipid breakdown in ischemic-reperfused heart. Isolated rat heart perfused by the Langendorff technique was subjected to 30 min of normothermic ischemia followed by 30 min of reperfusion. The experimental group received 0.6 mM deferoxamine, an iron chelator, before reperfusion of ischemic myocardium. Deacylation and reacylation of membrane phospholipids were monitored by using [14C]arachidonic acid (AA), whereas the de novo phospholipid synthesis was evaluated by using [3H]glycerol in the perfusate. In the deferoxamine group, the loss of [14C]phosphatidylcholine (PC) and the corresponding accumulation of isotopic lysophosphoglycerides as well as AA was significantly lower compared with the control. The incorporation of radioactivity for [14C]AA and [3H]glycerol into phospholipids was significantly increased in the treated group compared with the untreated group. In addition, decreased malonaldehyde formation and lactate dehydrogenase release, a higher recovery of high-energy phosphate compounds, and myocardial contractility were noticed in the deferoxamine-treated hearts. These results indicated that postischemic administration of an iron chelator such as deferoxamine can preserve membrane phospholipids and reduce myocardial dysfunction associated with reperfusion of ischemic heart.

Acylation↗