Oxidative stress
2150549
222530085
2008-06-29T21:00:12Z
Eric Kvaalen
122969
Note on weakness of analysis by Bjelakovic et al.
'''Oxidative stress''' is caused by an imbalance between the production of [[reactive oxygen species|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 [[redox|reducing environment]] within their cells. This reducing environment is preserved by [[enzyme]]s 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 [[peroxide]]s and [[free radical]]s that damage all components of the cell, including [[protein]]s, [[lipid]]s, 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 [[hormesis|mitohormesis]]. [[Reactive oxygen species]] can be beneficial, as they are used by the [[immune system]] as a way to attack and kill [[pathogen]]s. 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 [[Standard electrode potential|reduction potential]], or a large decrease in the reducing capacity of the cellular redox couples, such as [[glutathione]].<ref name="pmid11368918">{{cite journal |author=Schafer FQ, Buettner GR |title=Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple |journal=Free Radic. Biol. Med. |volume=30 |issue=11 |pages=1191–212 |year=2001 |pmid=11368918 |doi=}}</ref> 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]].<ref name="pmid2009322">{{cite journal |author=Lennon SV, Martin SJ, Cotter TG |title=Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli |journal=Cell Prolif. |volume=24 |issue=2 |pages=203–14 |year=1991 |pmid=2009322 |doi=}}</ref>
A particularly destructive aspect of oxidative stress is the production of [[reactive oxygen species]], which include [[free radical]]s and [[peroxide]]s. Some of the less reactive of these species (such as [[superoxide]]) can be converted by [[redox|oxidoreduction reactions]] with [[transition metal]]s or other redox cycling compounds (including [[quinone]]s) into more aggressive radical species that can cause extensive cellular damage.<ref>{{cite journal |author=Valko M, Morris H, Cronin MT |title=Metals, toxicity and oxidative stress |journal=Curr. Med. Chem. |volume=12 |issue=10 |pages=1161–208 |year=2005 |month=May |pmid=15892631 |doi=10.2174/0929867053764635}}</ref> The major portion of long term effects is inflicted by damage on DNA<ref>Evans MD, Cooke MS. Factors contributing to the outcome of oxidative damage to nucleic acids. Bioessays. 2004 May;26(5):533-42. Review. PMID: 15112233</ref>. Most of these oxygen-derived species are produced at a low level by normal [[cellular respiration|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 [[adenosine triphosphate|ATP]] depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.<ref name="pmid9801070">{{cite journal |author=Lelli JL, Becks LL, Dabrowska MI, Hinshaw DB |title=ATP converts necrosis to apoptosis in oxidant-injured endothelial cells |journal=Free Radic. Biol. Med. |volume=25 |issue=6 |pages=694–702 |year=1998 |pmid=9801070 |doi=}}</ref><ref name="pmid10391922">{{cite journal |author=Lee YJ, Shacter E |title=Oxidative stress inhibits apoptosis in human lymphoma cells |journal=J. Biol. Chem. |volume=274 |issue=28 |pages=19792–8 |year=1999 |pmid=10391922 |doi=}}</ref>
{| class="wikitable"
! Oxidant !! Description
|-
|•O<sub>2</sub>-, [[superoxide]] anion
|One-electron reduction state of O<sub>2</sub>, formed in many autoxidation reactions and by the [[electron transport chain]]. Rather unreactive but can release Fe<sup>2+</sup> from iron-sulfur proteins and [[ferritin]]. Undergoes dismutation to form H<sub>2</sub>O<sub>2</sub> spontaneously or by enzymatic catalysis and is a precursor for metal-catalyzed •OH formation.
|-
|H<sub>2</sub>O<sub>2</sub>, [[hydrogen peroxide]]
|Two-electron reduction state, formed by dismutation of •O<sub>2</sub>- or by direct reduction of O<sub>2</sub>. Lipid soluble and thus able to diffuse across membranes.
|-
|•OH, [[hydroxyl radical]]
|Three-electron reduction state, formed by [[Fenton's reagent|Fenton reaction]] and decomposition of [[peroxynitrite]]. Extremely reactive, will attack most cellular components
|-
|ROOH, [[peroxide|organic hydroperoxide]]
|Formed by radical reactions with cellular components such as [[lipid]]s and [[nucleobase]]s.
|-
|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<sub>2</sub>O<sub>2</sub> by [[myeloperoxidase]]. Lipid soluble and highly reactive. Will readily oxidize protein constituents, including [[thiol group]]s, [[amino group]]s and [[methionine]].
|-
|ONOO-, [[peroxynitrite]]
|Formed in a rapid reaction between •O<sub>2</sub>- 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.<ref>{{cite book |author=Sies, H. |chapter=Oxidative stress: introductory remarks |title=Oxidative Stress |editor=H. Sies, (Ed.) |publisher=Academic Press |locatrion=London |year=1985 |pages=1-7}}</ref><ref>{{cite book |author=Docampo, R. |chapter=Antioxidant mechanisms |title=Biochemistry and Molecular Biology of Parasites |editor=J. Marr and M. Müller, (Eds.) |publisher=Academic Press |location=London |year=1995 |pages=147-160}}</ref><ref name="pmid9189713">{{cite journal |author=Rice-Evans CA, Gopinathan V |title=Oxygen toxicity, free radicals and antioxidants in human disease: biochemical implications in atherosclerosis and the problems of premature neonates |journal=Essays Biochem. |volume=29 |issue= |pages=39–63 |year=1995 |pmid=9189713 |doi=}}</ref>
==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 [[cytochrome P450 oxidase|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 is not 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 disease]]s including [[Motor neuron disease|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 [[Atheromatous plaque|plaque]] formation. Oxidative stress also plays a role in the [[ischemic cascade]] due to oxygen reperfusion injury following [[Hypoxia (medical)|hypoxia]]. This cascade includes both [[strokes]] and [[heart attacks]].
==Antioxidants as supplements==
The use of [[antioxidants]] to prevent disease is controversial.<ref name="pmid8624173">{{cite journal |author=Meyers DG, Maloley PA, Weeks D |title=Safety of antioxidant vitamins |journal=Arch. Intern. Med. |volume=156 |issue=9 |pages=925–35 |year=1996 |pmid=8624173 |doi=}}</ref> In a high-risk group like smokers, high doses of [[Carotene|beta carotene]] increased the rate of lung cancer.<ref name="pmid16472151">{{cite journal |author=Ruano-Ravina A, Figueiras A, Freire-Garabal M, Barros-Dios JM |title=Antioxidant vitamins and risk of lung cancer |journal=Curr. Pharm. Des. |volume=12 |issue=5 |pages=599–613 |year=2006 |pmid=16472151 |doi=}}</ref> In less high-risk groups, the use of vitamin E appears to reduce the risk of [[heart disease]].<ref name="pmid10656300">{{cite journal |author=Pryor WA |title=Vitamin E and heart disease: basic science to clinical intervention trials |journal=Free Radic. Biol. Med. |volume=28 |issue=1 |pages=141–64 |year=2000 |pmid=10656300 |doi=}}</ref> In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is mixed.<ref name="pmid16227450">{{cite journal |author=Boothby LA, Doering PL |title=Vitamin C and vitamin E for Alzheimer's disease |journal=Ann Pharmacother |volume=39 |issue=12 |pages=2073–80 |year=2005 |pmid=16227450 |doi=10.1345/aph.1E495}}</ref><ref name="pmid15753151">{{cite journal |author=Kontush K, Schekatolina S |title=Vitamin E in neurodegenerative disorders: Alzheimer's disease |journal=Ann. N. Y. Acad. Sci. |volume=1031 |issue= |pages=249–62 |year=2004 |pmid=15753151 |doi=10.1196/annals.1331.025}}</ref> However, [[AstraZeneca]]'s radical scavenging [[nitrone]] drug [[NXY-059]] shows some efficacy in the treatment of stroke.<ref name="pmid16507608">{{cite journal |author=Fong JJ, Rhoney DH |title=NXY-059: review of neuroprotective potential for acute stroke |journal=Ann Pharmacother |volume=40 |issue=3 |pages=461–71 |year=2006 |pmid=16507608 |doi=10.1345/aph.1E636}}</ref>
Oxidative stress (as formulated in [[Denham Harman|Harman]]'s [[Free-radical theory|free radical theory of aging]]) is also thought to contribute to the aging process. While there is good evidence to support this idea in model organisms such as ''[[Drosophila melanogaster]]'' and ''[[Caenorhabditis elegans]]'',<ref name="pmid8415630">{{cite journal |author=Larsen PL |title=Aging and resistance to oxidative damage in Caenorhabditis elegans |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue=19 |pages=8905–9 |year=1993 |pmid=8415630 |doi= |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8415630}}</ref><ref name="pmid14616064">{{cite journal |author=Helfand SL, Rogina B |title=Genetics of aging in the fruit fly, Drosophila melanogaster |journal=Annu. Rev. Genet. |volume=37 |issue= |pages=329–48 |year=2003 |pmid=14616064 |doi=10.1146/annurev.genet.37.040103.095211}}</ref> 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.<ref>[http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413107002562 Publication demonstrating that oxidative stress is promoting life span]</ref> This process was previously named [[hormesis|mitohormesis]] or [[mitochondria]]l [[hormesis]] on a purely [[hypothetical]] basis.<ref name="pmid16242247">{{cite journal |author=Tapia PC |title=Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality |journal=Med. Hypotheses |volume=66 |issue=4 |pages=832–43 |year=2006 |pmid=16242247 |doi=10.1016/j.mehy.2005.09.009}}</ref> The situation in mammals is even less clear.<ref name="pmid12208343">{{cite journal |author=Sohal RS, Mockett RJ, Orr WC |title=Mechanisms of aging: an appraisal of the oxidative stress hypothesis |journal=Free Radic. Biol. Med. |volume=33 |issue=5 |pages=575–86 |year=2002 |pmid=12208343 |doi=}}</ref><ref name="pmid12086680">{{cite journal |author=Sohal RS |title=Role of oxidative stress and protein oxidation in the aging process |journal=Free Radic. Biol. Med. |volume=33 |issue=1 |pages=37–44 |year=2002 |pmid=12086680 |doi=}}</ref><ref name="pmid17090411">{{cite journal |author=Rattan SI |title=Theories of biological aging: genes, proteins, and free radicals |journal=Free Radic. Res. |volume=40 |issue=12 |pages=1230–8 |year=2006 |pmid=17090411 |doi=10.1080/10715760600911303}}</ref> Recent [[epidemiological]] findings support the process of [[mitohormesis]], and even suggest that antioxidants may increase disease [[prevalence]] in humans (although the results were influenced by studies on smokers).<ref name="pmid17327526">{{cite journal |author=Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C |title=Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis |journal=JAMA |volume=297 |issue=8 |pages=842–57 |year=2007 |pmid=17327526 |doi=10.1001/jama.297.8.842 |url=http://jama.ama-assn.org/cgi/content/full/297/8/842}}. See also the [http://jama.ama-assn.org/cgi/content/extract/298/4/401-a letter] to [[Journal of the American Medical Association|JAMA]] by [[Philip Taylor]] and [[Sanford Dawsey]] and the [http://jama.ama-assn.org/cgi/content/extract/298/4/402 reply] by the authors of the original paper.
</ref>
== 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 [[catalysis|catalyzes]] reactions that produce reactive [[radical (chemistry)|radical]]s and can produce [[reactive oxygen species]]. The most important reactions are probably [[H.J.H. Fenton|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 (e.g. 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 [[quinone]]s. Quinones can redox cycle with their conjugate [[semiquinone]]s and [[hydroquinone]]s, 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 [[phagocyte]]s producing both ROS and reactive nitrogen species. These include superoxide (•O<sub>2</sub>-), nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-).<ref name="pmid10922044">{{cite journal |author=Nathan C, Shiloh MU |title=Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=16 |pages=8841–8 |year=2000 |pmid=10922044 |doi= |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=34021&blobtype=pdf |format=PDF}}</ref> 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.<ref name="pmid9189713"/> This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.
==External links==
*[http://www.solid-gains.com/study/oxidative-stress/ Oxidative Stress - Relationship with Exercise and Training]
==See also==
* [[Acatalasia]]
* [[Nitric oxide]]
* [[Denham Harman]]
* [[Harry Demopoulos]]
* [[Michael Ristow]]
* [[Pro-oxidant]]
* [[Redox signaling]]
* [[hormesis|Mitohormesis]]
== References ==
{{reflist|2}}
[[Category:Cell biology]]
[[Category:Chemical pathology]]
[[de:Oxidativer Stress]]
[[es:Estrés oxidativo]]
[[fr:Stress oxydant]]
[[id:Stres oksidatif]]
[[it:Stress ossidativo]]
[[ms:Tekanan oksidatif]]
[[ja:活性酸素]]
[[pl:Stres oksydacyjny]]
[[pt:Stress oxidativo]]
[[ru:Оксидативный стресс]]
[[sv:Oxidativ stress]]
[[uk:Окислювальний стрес]]
[[zh:氧化应激]]