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
activity to form ROS. A novel therapeutic approach to suppress 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.
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