Department of Chemistry, Faculty of Natural Sciences, Constantine The Philosopher University, SK-949 74 Nitra, Slovakia. firstname.lastname@example.org
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.
Redox (reduction-oxidation) reactions include all chemical reactions in which atoms have their oxidation state changed
In chemistry, the oxidation state is an indicator of the degree of oxidation of an atom in a chemical compound.
Oxidative stress represents an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause dispruptions in normal mechanisms of cellular signaling
Carcinogenesis or oncogenesis or tumorigenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells. It is characterized by a progression of changes on cellular and genetic level that ultimately reprogram a cell to undergo uncontrolled cell division, thus forming a malignant mass.
Alternative theories of Cancer:
Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by epigenetic alterations (heritable and reversible changes other than the DNA sequence) or aneuploidy (numerical and structural abnormalities in chromosomes) rather than by mutations. Cancer has also been considered as a metabolic disease in which the cellular metabolism of oxygen is diverted from the pathway that generates energy (oxidative phosphorylation) to the pathway that generates reactive oxygen species (figure). This causes an energy switch from oxidative phosphorylation to aerobic glycolysis (Warburg's hypothesis) and the accumulation of reactive oxygen species leading to oxidative stress (oxidative stress theory of cancer). All these theories of carcinogenesis may be complementary rather than contradictory.
Next post will deal with the metal on metal links to oxidative stress.