Molecular bases of cellular iron toxicity12 1Guest Editor: Mario Comporti 2This article is part of a series of reviews on “Iron and Cellular Redox Status.” The full list of papers may be found on the homepage of the journal.

Eaton, John W.; Qian, Mingwei

doi:10.1016/s0891-5849(02)00772-4

Cited by 345 publications

(76 citation statements)

References 85 publications

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“…These authors proposed that the process of lipid peroxidation occurs via a free radical mechanism promoted by iron. Since then, the study of oxidation of lipids (or lipid peroxidation) has been a topic of many studies [42,63].…”

Section: Lipidsmentioning

confidence: 99%

Metals, Toxicity and Oxidative Stress

Valko

Morris²,

Cronin

2005

CMC

4,291

2,664

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Metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species, is reviewed. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). Whilst iron (Fe), copper (Cu), chromium (Cr), vanadium (V) and cobalt (Co) undergo redox-cycling reactions, for a second group of metals, mercury (Hg), cadmium (Cd) and nickel (Ni), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. However, a recent discovery that the upper limit of "free pools" of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to activation of mainly redox-sensitive transcription factors, involving NF-kappaB, AP-1 and p53. Antioxidants (both enzymatic and non-enzymatic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidation may be associated rather with the level of non-enzymatic antioxidants than the activity of enzymatic antioxidants. However, a very recent epidemiological study has shown that a daily intake of vitamin E of more than 400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in humans in vitro. Experimental results have also shown a link ...

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Section: Lipidsmentioning

confidence: 99%

Metals, Toxicity and Oxidative Stress

Valko

Morris²,

Cronin

2005

CMC

4,291

2,664

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“…It has been shown that lysosomes and mitochondria are particularly vulnerable to oxidative stress [169,170]. Intralysosomal redox-active iron is an important mediator of oxidant-induced cell death [163,171] as is supported by the marked protective effects of iron chelator [163,164].…”

Section: Recovering Ferritin Ironmentioning

confidence: 99%

Iron, Oxidative Stress and Early Neurological Deterioration in Ischemic Stroke

Carbonell¹,

Rama

2007

CMC

136

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Ischemic stroke is characterized by the disruption of cerebral blood flow, which produces a central core of dead neurons surrounded by a penumbra of damaged but partially functional neurons. Many factors are associated with such brain injury, including excitotoxicity and free radicals. Recent clinical studies have shown that high plasma ferritin levels are detrimental in acute ischemic stroke. As an iron-storage protein, ferritin can act both as a scavenger and as a donor of free iron, which is a source of hydroxyl radicals. Following disruption of the blood-brain barrier, the ferritin and the free iron that have accumulated in endothelial cells in brain capillaries, together with plasma ferritin, can enter the penumbra. Iron-dependent oxidative stress in the penumbra can lead to necrosis and further neurological deterioration following ischemic stroke. An excess of iron should be considered pathological in the ischemic brain. Therapeutic strategies for ischemic stroke should attempt to restore brain function within the penumbra. Consequently, the iron content of systemic stores should be measured, and anti-oxidant treatment should be considered when it is excessive.

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“…Iron-overload may lead to heart tissue damage through lipid peroxidation in response to oxidative stress, and a great diversity of toxic aldehydes are formed when lipid hydroperoxides break down in heart and plasma [8,9]. These agents are associated with toxic effects on intracellular organelles, and then cause either apoptotic or necrotic cell death [10]. There are many sources of ROS, including mitochondria, xanthine oxidase, uncoupled nitric oxide synthases and NADPH oxidases, all of them contribute to the development of cardiomyocyte hypertrophy [11].…”

Section: Introductionmentioning

confidence: 99%

Thrombopoietin Protects Cardiomyocytes from Iron-Overload Induced Oxidative Stress and Mitochondrial Injury

Chan

et al. 2015

Cell Physiol Biochem

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Background/Aims: Thalassaemia accompanied with iron-overload is common in Hong Kong. Iron-overload induced cardiomyopathy is the commonest cause of morbidity and mortality in patients with β-thalassaemia. Chronic iron-overload due to blood transfusion can cause cardiac failure. Decreased antioxidant defence and increased ROS production may lead to oxidative stress and cell injury. Iron-overload may lead to heart tissue damage through lipid peroxidation in response to oxidative stress, and a great diversity of toxic aldehydes are formed when lipid hydroperoxides break down in heart and plasma. Methods: Iron entry into embryonic heart H9C2 cells was determined by calcein assay using a fluorometer. Reactive oxygen species (ROS) production in cells treated with FeCl₃ or thrombopoietin (TPO) was monitored by using the fluorescent probe H₂DCFDA. Changes in mitochondrial membrane potential of H9C2 cells were quantified by using flow cytometry. Results: We demonstrated that iron induced oxidative stress and apoptosis in cardiomyocytes, and that iron increased ROS production and reduced cell viability in a dose-dependent manner. Iron treatment increased the proportion of cells with JC-1 monomers, indicating a trend of drop in the mitochondrial membrane potential. TPO exerted a cardio-protective effect on iron-induced apoptosis. Conclusions: These findings suggest that iron-overload leads to the generation of ROS and further induces apoptosis in cardiomyocytes via mitochondrial pathways. TPO might exert a protective effect on iron-overload induced apoptosis via inhibiting oxidative stress and suppressing the mitochondrial pathways in cardiomyocytes.

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Molecular bases of cellular iron toxicity12 1Guest Editor: Mario Comporti 2This article is part of a series of reviews on “Iron and Cellular Redox Status.” The full list of papers may be found on the homepage of the journal.

Cited by 345 publications

References 85 publications

Metals, Toxicity and Oxidative Stress

Metals, Toxicity and Oxidative Stress

Iron, Oxidative Stress and Early Neurological Deterioration in Ischemic Stroke

Thrombopoietin Protects Cardiomyocytes from Iron-Overload Induced Oxidative Stress and Mitochondrial Injury

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