Oxidative stress

Source: Wikipedia, the free encyclopedia.
xenobiotics
and the subsequent detoxification by cellular enzymes (termination).

Oxidative stress reflects an imbalance between the systemic manifestation of

cellular signaling
.

In humans, oxidative stress is thought to be involved in the development of

aging by induction of a process named mitohormesis,[20] and is required to initiate stress response processes in plants.[21]

Chemical and biological effects

Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione.[22] The effects of oxidative stress depend upon the size of these changes, with a cell being able to overcome small perturbations and regain its original state. However, more severe oxidative stress can cause cell death, and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.[23]

Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include

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).[26] Most of these oxygen-derived species are produced by normal aerobic metabolism. Normal cellular defense mechanisms destroy most of these. Repair of oxidative damages to DNA is frequent and ongoing, largely keeping up with newly induced damages. In rat urine, about 74,000 oxidative DNA adducts per cell are excreted daily.[27] There is also a steady state level of oxidative damages in the DNA of a cell. There are about 24,000 oxidative DNA adducts per cell in young rats and 66,000 adducts per cell in old rats.[27] 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.[28][29]

isoprostanes, hydroperoxy- and hydroxy- eicosatetraenoates, and 4-hydroxyalkenals.[31][33] While many of these products are used as markers of oxidative stress, the products derived from linoleic acid appear far more predominant than arachidonic acid products and therefore easier to identify and quantify in, for example, atheromatous plaques.[34] Certain linoleic acid products have also been proposed to be markers for specific types of oxidative stress. For example, the presence of racemic 9-HODE and 9-EE-HODE mixtures reflects free radical oxidation of linoleic acid whereas the presence of racemic 10-hydroxy-8E,12Z-octadecadienoic acid and 12-hydroxy-9Z-13-E-octadecadienoic acid reflects singlet oxygen attack on linoleic acid.[32][30] In addition to serving as markers, the linoleic and arachidonic acid products can contribute to tissue and/or DNA damage but also act as signals to stimulate pathways which function to combat oxidative stress.[31][35][36][37][38]

Oxidant Description
•O−
2, superoxide anion 		One-electron reduction state of O
2, formed in many autoxidation reactions and by the electron transport chain. Rather unreactive but can release Fe2+
 from iron-sulfur proteins and ferritin. Undergoes dismutation to form H
2O
2 spontaneously or by enzymatic catalysis and is a precursor for metal-catalyzed •OH formation.
H
2O
2, hydrogen peroxide 		Two-electron reduction state, formed by dismutation of •O−
2 or by direct reduction of O
2. Lipid-soluble and thus able to diffuse across membranes.
•OH, hydroxyl radical Three-electron reduction state, formed by Fenton reaction and decomposition of peroxynitrite. Extremely reactive, will attack most cellular components
ROOH, organic hydroperoxide Formed by radical reactions with cellular components such as lipids and nucleobases.
RO•, alkoxy and ROO•, peroxy radicals Oxygen centred organic radicals. Lipid forms participate in lipid peroxidation reactions. Produced in the presence of oxygen by radical addition to double bonds or hydrogen abstraction.
HOCl, hypochlorous acid Formed from H
2O
2 by
amino groups and methionine
.
ONOO-, peroxynitrite Formed in a rapid reaction between •O−
2 and NO•. Lipid-soluble and similar in reactivity to hypochlorous acid. Protonation forms peroxynitrous acid, which can undergo homolytic cleavage to form hydroxyl radical and nitrogen dioxide.

Table adapted from.[39][40][41]

Production and consumption of oxidants

One source of reactive oxygen under normal conditions in humans is the leakage of activated oxygen from

E. coli mutants that lack an active electron transport chain produce as much hydrogen peroxide as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms.[42] One possibility is that multiple redox-active flavoproteins all contribute a small portion to the overall production of oxidants under normal conditions.[43][44]

Other enzymes capable of producing superoxide are

redox signaling. Thus, to maintain proper cellular homeostasis
, a balance must be struck between reactive oxygen production and consumption.

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.[45] This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.

Diseases

Oxidative stress is suspected to be important in

Autism Spectrum Disorder.[48] Indirect evidence via monitoring biomarkers such as reactive oxygen species, and reactive nitrogen species production indicates oxidative damage may be involved in the pathogenesis of these diseases,[49][50] while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.[51]

Oxidative stress is thought to be linked to certain

immune evasion of leukemic cells. On the other hand, high levels of oxidative stress can also be selectively toxic to cancer cells.[53][54]

Oxidative stress is likely to be involved in age-related development of cancer. The reactive species produced in oxidative stress can cause direct damage to the DNA and are therefore

gastric cancer.[55]

Oxidative stress can cause DNA damage in neurons.[56] In neuronal progenitor cells, DNA damage is associated with increased secretion of amyloid beta proteins Aβ40 and Aβ42.[56] This association supports the existence of a causal relationship between oxidative DNA damage and Aβ accumulation and suggests that oxidative DNA damage may contribute to Alzheimer's disease (AD) pathology.[56] AD is associated with an accumulation of DNA damage (double-strand breaks) in vulnerable neuronal and glial cell populations from early stages onward,[57] and DNA double-strand breaks are increased in the hippocampus of AD brains compared to non-AD control brains.[58]

Antioxidants as supplements

Further information: Antioxidant

The use of antioxidants to prevent some diseases is controversial.

NXY-059 shows some efficacy in the treatment of stroke.[66]

Oxidative stress (as formulated in

mitohormesis, but a 2007 meta-analysis finds that in studies with a low risk of bias (randomization, blinding, follow-up), some popular antioxidant supplements (vitamin A, beta carotene, and vitamin E) may increase mortality risk (although studies more prone to bias reported the reverse).[73]

The USDA removed the table showing the

Oxygen Radical Absorbance Capacity (ORAC) of Selected Foods Release 2 (2010) table due to the lack of evidence that the antioxidant level present in a food translated into a related antioxidant effect in the body.[74]

Metal catalysts

Metals such as

Fenton reactions and the Haber-Weiss reaction, in which hydroxyl radical is generated from hydrogen peroxide.[76] 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 arginine, lysine, proline, and threonine. Excessive oxidative-damage leads to protein degradation or aggregation.[77][78]

The reaction of transition metals with proteins oxidated by reactive oxygen or 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.[79]

Non-metal redox catalysts

Certain organic compounds in addition to metal redox catalysts can also produce reactive oxygen species. One of the most important classes of these is the quinones. Quinones can redox cycle with their conjugate semiquinones and hydroquinones, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide.

Immune defense

The immune system uses the lethal effects of oxidants by making the production of oxidizing species a central part of its mechanism of killing pathogens; with activated phagocytes producing both reactive oxygen and nitrogen species. These include superoxide (•O−
2), nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-).[80] Although the use of these highly reactive compounds in the cytotoxic response of phagocytes causes damage to host tissues, the non-specificity of these oxidants is an advantage since they will damage almost every part of their target cell.[41] This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.

Male infertility

8-oxo-2'-deoxyguanosine is associated with abnormal spermatozoa and male infertility.[82]

Aging

Further information: Ageing

In a rat model of premature aging, oxidative stress induced

gerbil and human.[84] Further information on the association of oxidative DNA damage with aging is presented in the article DNA damage theory of aging. However, it was recently shown that the fluoroquinolone antibiotic Enoxacin can diminish aging signals and promote lifespan extension in nematodes C. elegans by inducing oxidative stress.[85]

Origin of eukaryotes

The

nuclear membrane.[86] Thus, the evolution of meiotic sex and eukaryogenesis may have been inseparable processes that evolved in large part to facilitate repair of oxidative DNA damages.[86][87][88]

COVID-19 and cardiovascular injury

It has been proposed that oxidative stress may play a major role in determining cardiac complications in COVID-19.[89][90]

See also

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