Elsevier

Toxicology

Volume 283, Issues 2–3, 10 May 2011, Pages 65-87
Toxicology

Review
Advances in metal-induced oxidative stress and human disease

https://doi.org/10.1016/j.tox.2011.03.001Get rights and content

Abstract

Detailed studies in the past two decades have shown that redox active metals like iron (Fe), copper (Cu), chromium (Cr), cobalt (Co) and other metals undergo redox cycling reactions and possess the ability to produce reactive radicals such as superoxide anion radical and nitric oxide in biological systems. Disruption of metal ion homeostasis may lead to oxidative stress, a state where increased formation of reactive oxygen species (ROS) overwhelms body antioxidant protection and subsequently induces DNA damage, lipid peroxidation, protein modification and other effects, all symptomatic for numerous diseases, involving cancer, cardiovascular disease, diabetes, atherosclerosis, neurological disorders (Alzheimer's disease, Parkinson's disease), chronic inflammation and others. The underlying mechanism of action for all these metals involves formation of the superoxide radical, hydroxyl radical (mainly via Fenton reaction) and other ROS, finally producing mutagenic and carcinogenic malondialdehyde (MDA), 4-hydroxynonenal (HNE) and other exocyclic DNA adducts. On the other hand, the redox inactive metals, such as cadmium (Cd), arsenic (As) and lead (Pb) show their toxic effects via bonding to sulphydryl groups of proteins and depletion of glutathione. Interestingly, for arsenic an alternative mechanism of action based on the formation of hydrogen peroxide under physiological conditions has been proposed. A special position among metals is occupied by the redox inert metal zinc (Zn). Zn is an essential component of numerous proteins involved in the defense against oxidative stress. It has been shown, that depletion of Zn may enhance DNA damage via impairments of DNA repair mechanisms. In addition, Zn has an impact on the immune system and possesses neuroprotective properties. The mechanism of metal-induced formation of free radicals is tightly influenced by the action of cellular antioxidants. Many low-molecular weight antioxidants (ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), glutathione (GSH), carotenoids, flavonoids, and other antioxidants) are capable of chelating metal ions reducing thus their catalytic acitivity to form ROS. A novel therapeutic approach to supress oxidative stress is based on the development of dual function antioxidants comprising not only chelating, but also scavenging components. Parodoxically, two major antioxidant enzymes, superoxide dismutase (SOD) and catalase contain as an integral part of their active sites metal ions to battle against toxic effects of metal-induced free radicals. The aim of this review is to provide an overview of redox and non-redox metal-induced formation of free radicals and the role of oxidative stress in toxic action of metals.

Abbreviations

NF-κB
nuclear factor kappa B
ATF
activating transcription factor
AP-1
activating protein
NFAT
nuclear factor of activated T-cells
IRPs
iron regulatory proteins
c-acon
aconitase
SOD
superoxide dismutase
HO-1
heme oxygenase
LIP
labile iron pool
8-OH-G
8-hydroxyguanine
ROOradical dot
peroxyl radicals
MDA
malondialdehyde
HNE
4-hydroxy-2-nonenal
NGAL
neutrophil gelatinase-associated lipocalin
HIF
hypoxia-inducible factor
VEGF
vascular endothelial growth factor
APP
amyloid precursor protein
NFT
neurofibrillary tangle
hCtr1
human copper transporter protein
HDL
high-density lipoprotein
LDL
low-density lipoprotein
TBARS
thiobarbituric acid-reactive substances
ONOO
peroxynitrite anion
STAT3
signal transducer and activator of transcription 3
IFN
interferon
IL
interleukin
MNC
mononuclear cells
TNF-alpha
tumour necrosis factor
VCAM-1
vascular cell adhesion molecule-1
ROS
reactive oxygen species
RNS
reactive nitrogen species
VEGF
vascular endothelial growth factor
GR
glutathione reductase
ALA
delta-aminolevulinic acid
DMSA
meso-2,3-dimercaptosuccinic acid
ALAD
deltaaminolevulinic acid dehydrogenase
DFB
deferoxamine
CQ
5-chloro-7-iodoquinolin-8-ol
BAL
dimercaprol

Keywords

Metals
Fenton chemistry
Toxicity
Free radicals
Antioxidants
Redox cycling
Oxidative stress

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