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PubMed1998

Antiproliferative effect of deferiprone on the Hep G2 cell line.

Iron is an essential element in cellular metabolism and the growth of all living species, and is involved in DNA replication. The risk of hepatocellular carcinoma development is associated with an increase in iron availability. The aim of the present work was to investigate the effect of an oral iron chelator, deferiprone (CP20), on HepG2 cell-line proliferation in culture. HepG2 cell cultures were maintained in the absence of fetal calf serum (FCS) and in the presence or not (control cultures) of CP20 at the concentrations of 50 or 100 microM; deferoxamine (DFO) was used as an iron chelator reference. Cell proliferation was investigated by the analysis of DNA synthesis using [3H] methyl-thymidine incorporation and of the cell cycle by flow cytometry. Iron chelation efficiency in the culture model was studied by analyzing the effect of CP20 on radioactive iron uptake, intracellular ferritin level, and transferrin receptor expression. CP20, at the concentration of 50 or 100 microM, inhibited DNA synthesis after 48 hr of incubation and induced an accumulation of the cells in the S phase of the cell cycle. Iron chelators inhibited cellular iron uptake, decreased intracellular ferritin level, and increased transferrin receptor protein and mRNA levels. Our results show that CP20 as well as deferoxamine inhibit HepG2 cell proliferation and block cell cycle in the S phase.

Cell Cycle↗

PubMed1998

Cytoprotective actions of estrogens against tert-butyl hydroperoxide-induced toxicity in hepatocytes.

Estrogens are effective antioxidants in diverse biological systems. Despite their antioxidant activities, it is not known yet whether estrogens prevent or alleviate liver toxicity induced by oxidative stress. In the present work, we studied this possibility by examining in vitro the protective potential of different estrogen compounds (17beta-estradiol, 2-hydroxyestradiol, and diethylstilbestrol) against tert-butyl hydroperoxide-induced hepatocyte damage. Various parameters such as cell viability, lipid peroxidation, adenine nucleotide content, and thiol status were measured as an index of cytotoxicity. The protective effects of estrogens were compared to those of the iron chelator deferoxamine. The molecules tested prevented oxidant-induced cell death differently, showing variable degrees of protection. Deferoxamine was the most potent agent, followed by diethylstilbestrol and 2-hydroxyestradiol, 17beta-estradiol being the least efficient. The inhibitory effects on lipid and thiol oxidations paralleled the effects on cell viability. The molecules also reduced the oxidant-induced ATP depletion, except for 17beta-estradiol which had no effect on the decreased ATP levels. Our results suggest that the mechanisms of the preventive actions of estrogens may be related not only to their antioxidant activity against free radicals, but also and to a lesser extent to the maintenance of the normal redox status of the cell, which partially recovers the intracellular GSH levels.

Adenosine Diphosphate↗

PubMed2001

Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells.

OBJECTIVE: Death of vascular smooth muscle cell (VSMC) induced by oxidized LDL (oxLDL) can occur by both necrosis and apoptosis which may contribute to plaque instability and rupture. Reactive oxygen species (ROS) induces apoptosis in VSMC and is involved in oxLDL action, we tested the hypothesis here that a coupling exists between ROS generation and apoptosis of oxLDL-treated VSMC. METHODS: Cultured VSMC from rat aorta were treated with oxLDL, apoptosis and necrosis were distinguished by using FITC-annexin V label and propidium iodide stain, analyzed by flow cytometry. ROS generation of VSMCs was detected by the fluorescence intensity of DCF. Apoptosis was also determined by cleavage of procaspase-3. RESULTS: OxLDL induced apoptosis (3 h) in a dose-dependent manner and reached maximum (with near-basal necrosis) at a concentration of 300 microg/ml. At this and lower (100 microg/ml) concentration, oxLDL, but not native LDL, stimulated ROS production rapidly (< or =5 min) and ROS level remained elevated for at least 45 min. Catalase and deferoxamine reduced both oxLDL-induced apoptosis and ROS generation. Superoxide dismutase and benzoic acid neither reduced the oxLDL-induced ROS generation nor inhibited apoptosis. Since oxLDL-induced ROS generation were inhibited by nordihydroguaiaretic acid and rotenone, lipoxygenase and mitochondrial pathways could be involved. In addition, catalase, deferoxamine, and N-acetylcysteine inhibited oxLDL-induced cleavage of procaspase-3 as well. CONCLUSIONS: ROS generation and apoptosis are tightly coupled in oxLDL-treated VSMCs. Antioxidants that reduced ROS level inhibited apoptosis, those that did not reduce ROS level were ineffective. Both mitochondrial and lipoxygenase activities may be involved.

Acetylation↗

PubMed1997

Cocaine-induced liver injury in mice is mediated by nitric oxide and reactive oxygen species.

The modulating effects of nitric oxide (NO) and reactive oxygen species on cocaine-induced hepatotoxicity were examined by measuring plasma alanine aminotransferase activity and by carrying out histological studies. Liver injury was induced by a single injection of cocaine in adult male ICR mice. Pretreatment with aminoguanidine (an inhibitor of NO synthase), N-methyl-D-glucamine dithiocarbamate complex with iron ion (II) (Fe2+(MGD)2, a trapping reagent of NO) or deferoxamine complex with iron ion (III) (Fe3+-deferoxamine, a scavenger of NO) produced a marked inhibition of the hepatotoxicity induced by cocaine. In addition, pretreatment with allopurinol (an inhibitor of xanthine oxidase) and 1,3-dimethylthiourea (a scavenger of hydroxyl radical) also produced a potent inhibition. These findings suggest that a hydroxyl radical produced by the reaction of NO and superoxide anion (O2-) via peroxynitrite may be involved in the pathogenesis of cocaine hepatotoxicity.

Allopurinol↗

PubMed1998

Acute intentional iron overdose in pregnancy.

BACKGROUND: Although iron is the second most common overdose agent in pregnancy, the obstetric literature does not reflect current management of this emergency. CASE: A 27-year-old woman, para 0-3-4-3, at 27 weeks' gestation ingested 24 mg/kg of elemental iron in a suicide attempt. Therapy with crystalloid hydration, gastric lavage, and intravenous deferoxamine chelation treated the overdose without maternal or fetal complications. CONCLUSION: Pregnancy should not alter therapy for acute iron overdose. Deferoxamine administered in the third trimester is not associated with perinatal complications and is potentially life saving.

Acute Disease↗

PubMed2001

Clinical management of beta-thalassemia major.

Management of patients with beta-thalassemia is based on adequate, safe blood transfusions (free of transfusion-transmitted diseases) and prevention of iron overload. Iron overload causes multiple endocrinopathies, contributes to osteoporosis, and is the cause of cardiac disease. Cardiac disease, secondary to iron damage, causes death in developed countries as a result of noncompliance to deferoxamine from the third decade of life. In underdeveloped countries, cardiac death starts from 12 years of age, due to nonavailability of deferoxamine. With the emergence of the advanced cardiac magnetic resonance imaging technique, early diagnosis of heart iron will allow the currently available iron-chelating agents (oral and parenteral) to be used in an innovative way to improve the quality of life and improve survival of patients with beta-thalassemia.

Disease Management↗

PubMed2001

Iron chelation therapy in sickle cell disease.

Iron chelation therapy with deferoxamine enhances iron excretion and removes excessive tissue iron in regularly transfused patients with sickle cell disease. Long-term studies of deferoxamine in other hemoglobinopathies demonstrate that regular chelation therapy also reduces iron-related organ damage and mortality. Careful design of chelation regimens and attention to compliance are critical elements of successful therapy. The role of new chelators in sickle cell disease is currently under Investigation.

Anemia, Sickle Cell↗

PubMed1999

Usefulness of the total iron binding capacity in the evaluation and treatment of acute iron overdose.

The ingestion of iron-containing products is a potential toxicologic emergency. The total iron binding capacity (TIBC) has been used widely as a predictor of end-organ toxicity and a guide to the need for deferoxamine therapy. When the TIBC is greater than the serum iron concentration (SIC), it is held that no free iron is present to cause toxicity. The TIBC fails as a marker of toxicity for several reasons. First, the laboratory methods used to measure TIBC are inaccurate in the setting of iron overload. Second, the presence of deferoxamine, the antidote for iron poisoning, has been shown to make the TIBC measurement inaccurate. Third, TIBC measurements have been shown to be variable. Finally, studies and case reports demonstrate toxicity even when the TIBC is greater than the SIC. These shortcomings of the TIBC invalidate it as a predictor of toxicity in iron poisoning.

Acute Disease↗

PubMed2000

Mechanism of dacron-activated monocytic cell oxidation of low density lipoprotein.

PURPOSE: Oxidized lipids are believed to contribute to atherogenesis and may play a role in the development of anastomotic intimal hyperplasia in prosthetic vascular grafts. This study examines the hypothesis that clinically relevant graft material activates monocytes to oxidize low density lipoprotein (LDL). METHODS: LDL and Dacron or expanded polytetrafluoroethylene (ePTFE) graft material were incubated in the presence of U937 cells, a monocytic cell line. LDL oxidation was measured by conjugated dienes, lipid peroxides, thiobarbituric acid-reacting substances, and electrophoretic mobility. Cell production of superoxide was measured by ferricytochrome c reduction. Metal ion requirement was assessed with the metal chelators, ethylenediaminetetra-acidic acid, deferoxamine, and bathocuproinedisulfonic acid. To determine whether human monocytes were capable of being activated by Dacron graft material to oxidize LDL, freshly isolated peripheral blood monocytes were also studied. RESULTS: Incubation of LDL with U937 cells and Dacron increased LDL oxidation by 5- to 20-fold. LDL incubated with ePTFE or U937 cells alone resulted in minimal oxidation. Dacron graft increased U937 cell production of superoxide by 4-fold, whereas ePTFE had no effect. Superoxide dismutase inhibited Dacron-activated U937 cell oxidation of LDL by greater than 50%, which indicates a role for superoxide. Ethylenediaminetetra-acidic acid, deferoxamine, and bathocuproinedisulfonic acid each inhibited Dacron-activated U937 cell oxidation of LDL. Human peripheral blood monocytes were activated by Dacron graft material to oxidize LDL; superoxide dismutase inhibited Dacron-activated human monocytic oxidation of LDL, which suggests a role for superoxide. CONCLUSION: These results suggest that Dacron graft material activates monocytes to oxidize LDL by a mechanism that involves superoxide and requires iron and copper ions. Our work suggests a mechanism by which lipids that have been deposited within implanted vascular grafts may become oxidized. Oxidized lipids may contribute to the cellular dysfunction that results in anastomotic intimal hyperplasia and graft failure.

Animals↗

PubMed2003

Iron chelators and iron toxicity.

Iron chelation may offer new approaches to the treatment and prevention of alcoholic liver disease. With chronic excess, either iron or alcohol alone may individually injure the liver and other organs. In combination, each exaggerates the adverse effects of the other. In alcoholic liver disease, both iron and alcohol contribute to the production of hepatic fibrosis through their effects on damaged hepatocytes, hepatic macrophages, hepatic stellate cells, and the extracellular matrix. The pivotal role of iron in these processes suggests that chelating iron may offer a new approach to arresting or ameliorating liver injury. For the past four decades, deferoxamine B mesylate has been the only iron-chelating agent generally available for clinical use. Clinical experience with deferoxamine has demonstrated the safety and effectiveness of iron chelation for the prevention and treatment of iron overload. Determined efforts to develop alternative agents have at last resulted in the development of a variety of candidate iron chelators that are now in or near clinical trial, including (a) the hexadentate phenolic aminocarboxylate HBED [N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid], (b) the tridentate desferrithiocin derivative 4'-OH-dadmDFT [4'-hydroxy-(S)-desazadesmethyl-desferrithiocin; (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-thiazolecarboxylic acid], (c) the tridentate triazole ICL670A [CGP72 670A; 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid], and (d) the bidentate hydroxypyridin-4-one deferiprone [L1, CP20; 1,2-dimethyl-3-hydroxypyridin-4-one]. These agents may provide new pharmacological means of averting or ameliorating liver damage in alcoholic liver disease by binding, inactivating, and eliminating the reactive forms of iron that contribute to oxidative injury of cellular components, are involved in signal transduction, or both.

Alcoholism↗

PubMed1997

Involvement of reactive oxygen species in the preservation injury to cultured liver endothelial cells.

We have previously demonstrated an energy-dependent injury to cultured liver endothelial cells during cold incubation in University of Wisconsin (UW) solution. In the present study, we report experimental evidence for the involvement of reactive oxygen species in this injury: LDH release during 48 h of cold incubation in UW solution was decreased from 40-55% under aerobic conditions to less than 20% under hypoxic conditions or by the presence of KCN (1 mM). Similar protection was achieved by the addition of the spin trap 5,5-dimethyl-1-pyrroline N-oxide, the hydroxyl radical scavenger dimethyl sulfoxide, or the flavonoid silibinin to UW solution under aerobic conditions. Preincubating the cells with the iron chelator deferoxamine even decreased the injury to less than 5%. The residual injury (as observed after longer incubation times) under hypoxic conditions or in cells preincubated with deferoxamine was no longer energy dependent. The amount of thiobarbituric acid-reactive substances markedly increased during cold incubation of the cells in UW solution. This increase was not observed in UW solution to which KCN had been added, i.e., under the conditions of energy depletion. These results suggest that an iron-dependent generation of reactive oxygen species with subsequent lipid peroxidation is involved in the pathogenesis of the injury to cultured liver endothelial cells in cold UW solution.

Animals↗

PubMed1999

Synergistic induction of hydroxyl radical-induced DNA single-strand breaks by chromium(VI) compound and cigarette smoke solution.

Chromium(VI) compounds and cigarette smoke are known human carcinogens. We found that K2Cr2O7 and cigarette smoke solution synergistically induced DNA single-strand breaks (0.23+/-0.04 breaks per DNA molecule) in pUC118 plasmid DNA. K2Cr2O7 alone or cigarette smoke solution alone induced much less strand breaks (0.03+/-0.01 or 0.07+/-0.02 breaks per DNA molecule, respectively). The synergistic effect was prevented by catalase and by hydroxyl radical scavengers such as deferoxamine, dimethylsulfoxide, d-mannitol, and Tris, but not by superoxide dismutase. Ascorbic acid enhanced the synergism. Glutathione inhibited strand breakage only at high concentrations. Electron spin resonance (ESR) studies using a hydroxyl radical trap demonstrated that hydroxyl radicals were generated when DNA was incubated with K2Cr2O7 and cigarette smoke solution. Hydroxyl radical adduct decreased dose-dependently when strand breakage was prevented by catalase, deferoxamine, dimethylsulfoxide, d-mannitol or Tris, but not significantly by superoxide dismutase. We also used ESR spectroscopy to study the effects of different concentration of ascorbic acid and glutathione. The results showed that hydroxyl radical, which is proposed as a main carcinogenic mechanism for both chromium(VI) compounds and cigarette smoke solution was mainly responsible for the DNA breaks they induced.

Antioxidants↗

PubMed2000

Stress- and growth-related gene expression are independent of chemical-induced prostaglandin E(2) synthesis in renal epithelial cells.

Cellular stress can initiate prostaglandin (PG) biosynthesis which, through changes in gene expression, can modulate cellular functions, including cell growth. PGA(2), a metabolite of PGE(2), induces the expression of stress response genes, including gadd153 and hsp70, in HeLa cells and human diploid fibroblasts. PGs, gadd153, and hsp70 expression are also influenced by the cellular redox status. Polyphenolic glutathione conjugates retain the ability to redox cycle, with the concomitant generation of reactive oxygen species. One such conjugate, 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), is a potent nephrotoxic and nephrocarcinogenic metabolite of the nephrocarcinogen, hydroquinone. We therefore investigated the effects of TGHQ on PGE(2) synthesis and gene expression in a renal proximal tubular epithelial cell line (LLC-PK(1)). TGHQ (200 microM, 2 h) increases PGE(2) synthesis (2-3-fold) in LLC-PK(1) cells with only minor (5%) reductions in cell viability. This response is toxicant-specific, since another proximal tubular toxicant, S-(1, 2-dichlorovinyl)-L-cysteine (DCVC), stimulates PGE(2) synthesis only after massive (68%) reductions in cell viability. Consistent with the ability of TGHQ to generate an oxidative stress, both deferoxamine mesylate and catalase protect LLC-PK(1) cells from TGHQ-mediated cytotoxicity. Only catalase, however, completely blocks TGHQ-mediated PGE(2) synthesis, implying a major role for hydrogen peroxide in this response. TGHQ induces the early (60 min) expression of gadd153 and hsp70. However, while inhibition of cyclooxygenase with aspirin prevents TGHQ-induced PGE(2) synthesis, it does not affect TGHQ-mediated induction of gadd153 or hsp70 expression. In contrast, a stable PGE(2) analogue, 11-deoxy-16, 16-dimethyl-PGE(2) (DDM-PGE(2)), which protects LLC-PK(1) cells against TGHQ-mediated cytotoxicity, modestly elevates the levels of gadd153 and hsp70 expression. In addition, catalase and, to a lesser extent, deferoxamine mesylate block TGHQ-induced gene expression. Therefore, although TGHQ-induced generation of reactive oxygen species is required for PGE(2) synthesis and stress gene expression, acute TGHQ-mediated increases in gadd153 and hsp70 mRNA levels are independent of PGE(2) synthesis.

Animals↗

PubMed1997

Inhibition of Fe(II) catalyzed linoleic acid oxidation and DNA damage by phosvitin.

The oxidation of linoleic acid catalyzed by Fe(II) is strongly inhibited by phosvitin, while chelation with EDTA, NTA or deferoxamine produced only partial inhibition. Interestingly, the DNA degradation catalyzed by Fe(II) in the presence of H2O2 is also inhibited by phosvitin or deferoxamine. In contrast, chelation of the metal ion with EDTA or NTA enhanced the DNA degradation. The results suggest that the nature of interaction between the metal ion and the complexing agent may be an important factor in the generation of active oxygen intermediates.

Animals↗

PubMed2000

Cognitive deficits in beta-thalassemia major.

OBJECTIVES: To assess cognitive functioning in patients affected by beta-thalassemia major (beta-th) by using a neuropsychological battery, and to identify clinical correlates. MATERIAL AND METHODS: Forty-six beta-th patients and 46 controls similar for age, sex, and education participated in the study. All subjects performed a comprehensive neuropsychological battery including tests of abstract reasoning, attention, executive functions, language, constructional/visuospatial skills, and memory. RESULTS: Compared to controls beta-th patients, in particular those showing signs of hemosiderosis, were significantly impaired on all neuropsychological tests. There was no relationship between cognitive performances and signs of deferoxamine toxicity, deferoxamine dosage, and levels of hemoglobin and ferritin, while duration of transfusional therapy and time interval between onset of blood transfusions and onset of chelating treatment correlated with performances of tests assessing abstract reasoning, attention, constructional/visuospatial skills, memory and with the scores of the Mini Mental State Examination. CONCLUSION: Our findings suggest that beta-th is associated with neuropsychological impairment involving multiple cognitive domains and argue for a potential role of hemosiderosis on cognitive functioning.

Adult↗

PubMed1992

Mesangial cell killing by leukocytes: role of leukocyte oxidants and proteolytic enzymes.

Mesangial cells from human and rat kidney were examined for sensitivity to killing by neutrophils. Cells from both species were sensitive to killing by phorbol myristate acetate-stimulated neutrophils. Catalase was highly protective while superoxide dismutase was less protective and a number of protease inhibitors were not protective. Strong protection was also observed with the iron chelators, deferoxamine and phenanthroline, and with the hydroxyl radical scavengers, dimethylthiourea and 5,5-dimethyl-1-pyrroline N-oxide. Pretreatment of the mesangial cells with deferoxamine followed by washing also provided protection. Mesangial cells were also killed by reagent hydrogen peroxide (H2O2) but were much less sensitive to injury by direct application of proteolytic enzymes. The ability of H2O2 to injure mesangial cells was prevented by pre-incubation of the H2O2 with human leukocyte myeloperoxidase. These data suggest that killing is due primarily to the generation of H2O2 by the stimulated neutrophils and its further reduction in an iron-catalyzed reaction. The hydroxyl radical may be the reduction product that actually mediates lethal injury but lack of scavenger specificity prevents definitively concluding this. Mesangial cell killing by activated neutrophils could be significantly inhibited by monoclonal antibodies to CD11/CD18 molecules, suggesting that close contact between the target and effector cells is required for cytotoxicity. Although qualitatively similar to endothelial cells, the mesangial cells appeared to be quantitatively more oxidant sensitive than previously examined human and rat endothelial cells. Taken together, these data show that mesangial cells from rat and human are sensitive to leukocyte-induced injury and that injury results via an oxidant pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1999

Induction of reactive oxygen intermediates in human monocytes by tumour cells and their role in spontaneous monocyte cytotoxicity.

The present study examined the ability of human monocytes to produce reactive oxygen intermediates after a contact with tumour cells. Monocytes generated oxygen radicals, as measured by luminol-enhanced chemiluminescence and superoxide anion production, after stimulation with the tumour, but not with untransformed, cells. The use of specific oxygen radical scavengers and inhibitors, superoxide dismutase, catalase, dimethyl sulphoxide and deferoxamine as well as the myeloperoxidase inhibitor 4-aminobenzoic acid hydrazide, indicated that chemiluminescence was dependent on the production of superoxide anion and hydroxyl radical and the presence of myeloperoxidase. The tumour cell-induced chemiluminescent response of monocytes showed different kinetics from that seen after activation of monocytes with phorbol ester. These results indicate that human monocytes can be directly stimulated by tumour cells for reactive oxygen intermediate production. Spontaneous monocyte-mediated cytotoxicity towards cancer cells was inhibited by superoxide dismutase, catalase, deferoxamine and hydrazide, implicating the role of superoxide anion, hydrogen peroxide, hydroxyl radical and hypohalite. We wish to suggest that so-called 'spontaneous' tumoricidal capacity of freshly isolated human monocytes may in fact be an inducible event associated with generation of reactive oxygen intermediates and perhaps other toxic mediators, resulting from a contact of monocytes with tumour cells.

Adenocarcinoma↗

PubMed1998

Effects of inhibitors of the activity of poly (ADP-ribose) synthetase on the liver injury caused by ischaemia-reperfusion: a comparison with radical scavengers.

1. Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA which are caused by reactive oxygen species (ROS) and peroxynitrite. Excessive activation of PARS may contribute to the hepatocyte injury caused by ROS in vitro and inhibitors of PARS activity reduce the degree of reperfusion injury of the heart, skeletal muscle and brain in vivo. Here we compared the effects of various inhibitors of the activity of PARS with those of deferoxamine (an iron chelator which prevents the generation of hydroxyl radicals) and tiron (an intracellular scavenger of superoxide anion) on the degree of hepatic injury caused by ischaemia and reperfusion of the liver in the anaesthetized rat or rabbit. 2. In the rat, ischaemia (30 or 60 min) and reperfusion (120 min) of the liver resulted in significant increases in the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) indicating the development of liver injury. Intravenous administration of the PARS inhibitors 3-aminobenzamide (3-AB, 10 mg kg(-1) or 30 mg kg(-1)), 1,5-dihydroxyisoquinoline (ISO, 1 mg kg(-1)) or 4-amino-1,8-naphthalimide (4-AN, 3 mg kg(-1)) before reperfusion did not reduce the degree of liver injury caused by ischaemia-reperfusion. 3. In contrast to the PARS inhibitors, deferoxamine (40 mg kg(-1)) or tiron (300 mg kg(-1)) significantly attenuated the rise in the serum levels of AST and ALT caused by ischaemia-reperfusion of the liver of the rat. 4. In the rabbit, the degree of liver injury caused by ischaemia (60 min) and reperfusion (120 min) was also not affected by 3-AB (10 mg kg(-1)) or ISO (1 mg kg(-1)). 5. These results support the view that the generation of oxygen-derived free radicals mediates the liver injury associated with reperfusion of the ischaemic liver by mechanism(s) which are independent of the activation of PARS.

Animals↗