Everything about Oxidative Stress totally explained
Oxidative stress is caused by an imbalance between the production of
reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. All forms of
life maintain a
reducing environment within their cells. This reducing environment is preserved by
enzymes that maintain the reduced state through a constant input of metabolic energy. Disturbances in this normal redox state can cause toxic effects through the production of
peroxides and
free radicals that damage all components of the cell, including
proteins,
lipids, and
DNA.
In humans, oxidative stress is involved in many diseases, such as
atherosclerosis,
Parkinson's disease and
Alzheimer's disease, but it may also be important in prevention of
aging by induction of a process named
mitohormesis.
Reactive oxygen species can be beneficial, as they're used by the
immune system as a way to attack and kill
pathogens. Reactive oxygen species are also used in
cell signaling. This is dubbed
redox signaling.
Chemical and biological effects
In chemical terms, oxidative stress is a large increase (becoming less negative) in the cellular
reduction potential, or a large decrease in the reducing capacity of the cellular redox couples, such as
glutathione. 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.
A particularly destructive aspect of oxidative stress is the production of
reactive oxygen species, which 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 of these oxygen-derived species are produced at a low level by normal
aerobic metabolism and the damage they cause 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.
| Oxidant |
Description |
| •O2-, superoxide anion |
One-electron reduction state of O2, 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 H2O2 spontaneously or by enzymatic catalysis and is a precursor for metal-catalyzed •OH formation. |
| H2O2, hydrogen peroxide |
Two-electron reduction state, formed by dismutation of •O2- or by direct reduction of O2. 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 H2O2 by myeloperoxidase. Lipid soluble and highly reactive. Will readily oxidize protein constituents, including thiol groups, amino groups and methionine. |
| ONOO-, peroxynitrite |
Formed in a rapid reaction between •O2- 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.
Production and consumption of oxidants
The most important source of reactive oxygen under normal conditions in aerobic organisms is probably the leakage of activated oxygen from
mitochondria during normal oxidative respiration.
Other enzymes capable of producing superoxide are
xanthine oxidase, NADPH oxidases and
cytochromes P450. Hydrogen peroxide is produced by a wide variety of enzymes including several oxidases. Reactive oxygen species play important roles in cell signalling, a process termed
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 isn't their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.
Oxidative stress contributes to tissue injury following irradiation and
hyperoxia. It is suspected (though not proven) to be important in
neurodegenerative diseases including
Lou Gehrig's disease (aka MND or ALS),
Parkinson's disease,
Alzheimer's disease, and
Huntington's disease. Oxidative stress is thought to be linked to certain
cardiovascular disease, since oxidation of
LDL in the vascular
endothelium is a precursor to
plaque formation. Oxidative stress also plays a role in the
ischemic cascade due to oxygen reperfusion injury following
hypoxia. This cascade includes both
strokes and
heart attacks.
Antioxidants as supplements
The use of
antioxidants to prevent disease is controversial. In a high-risk group like smokers, high doses of
beta carotene increased the rate of lung cancer. In less high-risk groups, the use of vitamin E appears to reduce the risk of
heart disease. In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is mixed. However,
AstraZeneca's radical scavenging
nitrone drug
NXY-059 shows some efficacy in the treatment of stroke.
Oxidative stress (as formulated in
Harman's
free radical theory of aging) is also thought to contribute to the aging process. While there's good evidence to support this idea in model organisms such as
Drosophila melanogaster and
Caenorhabditis elegans, recent evidence from
Michael Ristow's laboratory suggests that oxidative stress may also promote life expectancy of
Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species. This process was previously named
mitohormesis or
mitochondrial
hormesis on a purely
hypothetical basis. The situation in mammals is even less clear. Recent
epidemiological findings support the process of
mitohormesis, and even suggest that antioxidants may increase disease
prevalence in humans.
Metal catalysts
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 reactions that produce reactive
radicals and can produce
reactive oxygen species. The most important reactions are probably
Fenton's reaction and the Haber-Weiss reaction, in which
hydroxyl radical is produced from reduced iron and hydrogen peroxide. The hydroxyl radical then can lead to modifications of amino acids (for example meta-
tyrosine and ortho-
tyrosine formation from
phenylalanine), carbohydrates, initiate lipid peroxidation, and oxidize nucleobases. Most enzymes that produce reactive oxygen species contain one of these metals. 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. In humans,
hemochromatosis is associated with increased tissue iron levels,
Wilson's disease with increased tissue levels of copper. and chronic
manganism with exposure to manganese ores.
Non-metal redox catalysts
Certain organic compounds in addition to metal redox catalyts can also produce reactive oxygen species. One of the most important classes of these are 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. Oxidative stress generated by the reducing agent
uric acid may be involved in the
Lesch-Nyhan syndrome,
stroke, and
metabolic syndrome. Likewise, production of reactive oxygen species in the presence of
homocysteine may figure in
homocystinuria, as well as
atherosclerosis,
stroke, and
Alzheimers.
Immune defence
The immune system uses the lethal effects of oxidants by making production of oxidizing species a central part of its mechanism of killing pathogens; with activated
phagocytes producing both ROS and reactive nitrogen species. These include superoxide (•O
2-), nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-). 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 that'll damage almost every part of their target cell.
This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.
Further Information
Get more info on 'Oxidative Stress'.
|
External Link Exchanges
Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:
<a href="http://oxidative_stress.totallyexplained.com">Oxidative stress Totally Explained</a>
Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned. |
