Reactive oxygen species (ROS), byproducts of oxygen metabolism, are present in the cells as a consequence of living in an oxygen-rich atmosphere. ROS can be generated by both endogenous and exogenous sources, such as mitochondria and carcinogens, respectively.
ROS contain superoxide (O2•−) and hydrogen peroxide (H2O2), and are important for the normal function of many cellular processes, including metabolism, cell growth and differentiation, immune responses and apoptosis.
Low levels of ROS serve as secondary messengers and are essential for carrying out these cellular functions.
Overproduction of ROS and generation of highly reactive ROS, for example hydroxyl (•OH) radicals, can attack lipids, protein, DNA, and other cellular components, leading to numerous diseases, among them cancer, and cardiovascular and neurological disorders.
In humans, oxidative stress is thought to be involved in the development of Asperger syndrome, ADHD,cancer, Parkinson’s disease, Lafora disease,Alzheimer’s disease, atherosclerosis, heart failure,myocardial infarction, fragile X syndrome,Sickle Cell Disease, lichen planus, vitiligo,autism, infection, Chronic fatigue syndrome, and Depression. However, reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens. Short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis.
Exposure to genotoxic agents in the environment such as ionizing radiation, UV, and chemical carcinogens leads to DNA damage. Additionally, some endogenous agents derived from cellular metabolism such as reactive oxygen species (ROS) also frequently damage DNA. DNA damage is cytotoxic and genotoxic, which can result in acute cell killing or prolonged deleterious biological effects that include chromosomal aberrations, gene mutations, cancer, neurodegeneration, and aging. Cells contain complex systems in response to DNA damage.
Metals such as iron, copper, chromium, vanadium, and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes production of reactive radicals and reactive oxygen species. The presence of such metals in biological systems in an uncomplexed form (not in a protein or other protective metal complex) can significantly increase the level of oxidative stress. These metals are thought to induce Fenton reactions and the Haber-Weiss reaction, in which hydroxyl radical is generated from hydrogen peroxide. The hydroxyl radical then can modify amino acids. For example, meta-tyrosine and ortho-tyrosine form by hydroxylation of phenylalanine. Other reactions include lipid peroxidation and oxidation of nucleobases. Metal catalyzed oxidations also lead to irreversible modification of R (Arg), K (Lys), P (Pro) and T (Thr) Excessive oxidative-damage leads to protein degradation or aggregation.
The reaction of transition metals with proteins oxidated by Reactive Oxygen Species or Reactive Nitrogen Species can yield reactive products that accumulate and contribute to aging and disease. For example, in Alzheimer’s patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells.
Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include free radicals and peroxides. Some of the less reactive of these species (such as superoxide) can be converted by oxidoreduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage. Most long-term effects are caused by damage to DNA. DNA damage induced by ionizing radiation is similar to oxidative stress, and these lesions have been implicated in aging and cancer. Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol, have been extensively studied. Recently the focus has shifted to some of the more complex lesions. Tandem DNA lesions are formed at substantial frequency by ionizing radiation and metal-catalyzed H2O2 reactions. Under anoxic conditions, the predominant double-base lesion is a species in which C8 of guanine is linked to the 5-methyl group of an adjacent 3′-thymine (G[8,5- Me]T). Most of these oxygen-derived species are produced at a low level by normal aerobic metabolism. Normal cellular defense mechanisms destroy most of these. Likewise, any damage to cells is constantly repaired. However, under the severe levels of oxidative stress that cause necrosis, the damage causes ATP depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.
The best studied cellular antioxidants are the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.
The amino acid methionine is prone to oxidation, but oxidized methionine can be reversible. Oxidation of methionine is shown to inhibit the phosphorylation of adjacent Ser/Thr/Tyr sites in proteins. This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.