Antioxidant 3277 224896610 2008-07-10T22:04:08Z Cakulbet 1330710 [[WP:UNDO|Undid]] revision 224893811 by [[Special:Contributions/76.182.206.208|76.182.206.208]] ([[User talk:76.182.206.208|talk]]) [[Image:Glutathione-3D-vdW.png|thumb|right|350px|Space-filling model of the antioxidant [[metabolomics|metabolite]] [[glutathione]]. The yellow sphere is the [[redox|redox-active]] sulfur atom that provides antioxidant activity, while the red, blue, white, and dark grey spheres represent oxygen, nitrogen, hydrogen, and carbon atoms, respectively.]] An '''antioxidant''' is a [[molecule]] capable of slowing or preventing the [[Redox|oxidation]] of other molecules. Oxidation is a [[chemical reaction]] that transfers [[electron]]s from a substance to an [[oxidizing agent]]. Oxidation reactions can produce [[free radical]]s, which start [[chain reaction]]s that damage [[cell (biology)|cells]]. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often [[reducing agent]]s such as [[thiol]]s or [[polyphenol]]s. Although oxidation reactions are crucial for life, they can also be damaging; hence, [[plant]]s and [[animal]]s maintain complex systems of multiple types of antioxidants, such as [[glutathione]], [[vitamin C]], and [[vitamin E]] as well as [[enzyme]]s such as [[catalase]], [[superoxide dismutase]] and various [[peroxidase]]s. Low levels of antioxidants, or [[enzyme inhibitor|inhibition]] of the antioxidant enzymes, causes [[oxidative stress]] and may damage or kill cells. As oxidative stress might be an important part of many human diseases, the use of antioxidants in [[pharmacology]] is intensively studied, particularly as treatments for [[stroke]] and [[neurodegenerative disease]]s. However, it is unknown whether oxidative stress is the cause or the consequence of disease. Antioxidants are also widely used as ingredients in [[dietary supplements]] in the hope of maintaining health and preventing diseases such as [[cancer]] and [[coronary heart disease]]. Although some studies have suggested antioxidant supplements have health benefits, other large [[clinical trial]]s did not detect any benefit for the formulations tested, and excess supplementation may be harmful.<ref>{{cite journal |author=Bjelakovic G, et al |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}}</ref> In addition to these uses in medicine, antioxidants have many industrial uses, such as [[preservatives]] in food and cosmetics and preventing the degradation of [[rubber]] and [[gasoline]]. ==History== The term antioxidant originally was used to refer specifically to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th century, extensive study was devoted to the uses of antioxidants in important industrial processes, such as the prevention of metal [[corrosion]], the [[vulcanization]] of rubber, and the [[polymerization]] of fuels in the [[fouling]] of [[internal combustion engine]]s.<ref>Matill HA (1947). Antioxidants. ''Annu Rev Biochem'' 16: 177–192.</ref> Early research on the role of antioxidants in biology focused on their use in preventing the oxidation of [[unsaturated fat]]s, which is the cause of [[rancidity]].<ref>{{cite journal |author=German J |title=Food processing and lipid oxidation |journal=Adv Exp Med Biol |volume=459 |issue= |pages=23–50 |year=1999 |pmid=10335367}}</ref> Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However, it was the identification of [[Vitamin A|vitamins A]], [[Vitamin C|C]], and [[Vitamin E|E]] as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in the biochemistry of living organisms.<ref>{{cite journal |author=Jacob R |title=Three eras of vitamin C discovery |journal=Subcell Biochem |volume=25 |issue= |pages=1–16 |year=1996 |pmid=8821966}}</ref><ref>{{cite journal |author=Knight J |title=Free radicals: their history and current status in aging and disease |journal=Ann Clin Lab Sci |volume=28 |issue=6 |pages=331–46 |year=1998 |pmid=9846200}}</ref> The possible [[mechanisms of action]] of antioxidants were first explored when it was recognized that a substance with anti-oxidative activity is likely to be one that is itself readily oxidized.<ref>Moreau and Dufraisse, (1922) ''Comptes Rendus des Séances et Mémoires de la Société de Biologie'', '''86''', 321.</ref> Research into how [[vitamin E]] prevents the process of [[lipid peroxidation]] led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by [[scavenger (chemistry)|scavenging]] [[reactive oxygen species]] before they can damage cells.<ref>{{cite journal |author=Wolf G |title=The discovery of the antioxidant function of vitamin E: the contribution of Henry A. Mattill |url=http://jn.nutrition.org/cgi/content/full/135/3/363 |journal=J Nutr |volume=135 |issue=3 |pages=363–6 |year=2005 |pmid=15735064}}</ref> ==The oxidative challenge in biology== {{further|[[Oxidative stress]]}} [[Image:L-ascorbic-acid-3D-balls.png|thumb|right|250px|The structure of the antioxidant [[vitamin]] [[ascorbic acid]] (vitamin C).]] A [[paradox]] in metabolism is that while the vast majority of complex life requires [[oxygen]] for its existence, oxygen is a highly reactive molecule that damages living organisms by producing [[reactive oxygen species]].<ref name=Davies>{{cite journal |author=Davies K |title=Oxidative stress: the paradox of aerobic life |journal=Biochem Soc Symp |volume=61 |issue= |pages=1–31 |year=1995 |pmid=8660387}}</ref> Consequently, organisms contain a complex network of antioxidant [[metabolite]]s and [[enzyme]]s that work together to prevent oxidative damage to cellular components such as [[DNA]], [[protein]]s and [[lipid]]s.<ref name=Sies>{{cite journal |author=Sies H |title=Oxidative stress: oxidants and antioxidants |url=http://ep.physoc.org/cgi/reprint/82/2/291.pdf |journal=Exp Physiol |volume=82 |issue=2 |pages=291–5 |year=1997 |pmid=9129943}}</ref><ref name=Vertuani>{{cite journal |author=Vertuani S, Angusti A, Manfredini S |title=The antioxidants and pro-antioxidants network: an overview |journal=Curr Pharm Des |volume=10 |issue=14 |pages=1677–94 |year=2004 |pmid=15134565 |doi=10.2174/1381612043384655}}</ref> In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell.<ref name=Sies/><ref name=Davies/> The reactive oxygen species produced in cells include [[hydrogen peroxide]] (H<sub>2</sub>O<sub>2</sub>), [[hypochlorous acid]] (HClO), and [[free radicals]] such as the [[hydroxyl radical]] (·OH) and the [[superoxide|superoxide anion]] (O<sub>2</sub><sup>−</sup>).<ref name = "emfafb">{{cite journal |author=Valko M, Leibfritz D, Moncol J, Cronin M, Mazur M, Telser J |title=Free radicals and antioxidants in normal physiological functions and human disease |journal=Int J Biochem Cell Biol |volume=39 |issue=1 |pages=44–84 |year=2007 |pmid=16978905 |doi=10.1016/j.biocel.2006.07.001}}</ref> The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. This species is produced from hydrogen peroxide in [[catalysis|metal-catalyzed]] redox reactions such as the [[Fenton reaction]].<ref>{{cite journal |author=Stohs S, Bagchi D |title=Oxidative mechanisms in the toxicity of metal ions |journal=Free Radic Biol Med |volume=18 |issue=2 |pages=321–36 |year=1995 |pmid=7744317 |doi=10.1016/0891-5849(94)00159-H}}</ref> These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins.<ref name=Sies/> Damage to DNA can cause [[mutation]]s and possibly [[cancer]], if not reversed by [[DNA repair]] mechanisms,<ref>{{cite journal |author=Nakabeppu Y, Sakumi K, Sakamoto K, Tsuchimoto D, Tsuzuki T, Nakatsu Y |title=Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids |journal=Biol Chem |volume=387 |issue=4 |pages=373–9 |year=2006 |pmid=16606334 |doi=10.1515/BC.2006.050}}</ref><ref>{{cite journal |author=Valko M, Izakovic M, Mazur M, Rhodes C, Telser J |title=Role of oxygen radicals in DNA damage and cancer incidence |journal=Mol Cell Biochem |volume=266 |issue=1–2 |pages=37–56 |year=2004 |pmid=15646026 |doi=10.1023/B:MCBI.0000049134.69131.89}}</ref> while damage to [[protein]]s causes enzyme inhibition, [[denaturation (biochemistry)|denaturation]] and [[proteasome|protein degradation]].<ref>{{cite journal |author=Stadtman E |title=Protein oxidation and aging |journal=Science |volume=257 |issue=5074 |pages=1220–4 |year=1992 |pmid=1355616 |doi=10.1126/science.1355616}}</ref> The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.<ref name=Raha>{{cite journal |author=Raha S, Robinson B |title=Mitochondria, oxygen free radicals, disease and aging |journal=Trends Biochem Sci |volume=25 |issue=10 |pages=502–8 |year=2000 |pmid=11050436 |doi=10.1016/S0968-0004(00)01674-1}}</ref> In this process, the superoxide anion is produced as a by-product of several steps in the [[electron transport chain]].<ref>{{cite journal |author=Lenaz G |title=The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology |journal=IUBMB Life |volume=52 |issue=3–5 |pages=159–64 |year=2001 |pmid=11798028 |doi=10.1080/15216540152845957}}</ref> Particularly important is the reduction of [[coenzyme Q]] in [[complex III]], since a highly reactive free radical is formed as an intermediate (Q'''·'''<sup>−</sup>). This unstable intermediate can lead to electron "leakage", when electrons jump directly to oxygen and form the superoxide anion, instead of moving through the normal series of well-controlled reactions of the electron transport chain.<ref>{{cite journal | author=Finkel T, Holbrook NJ | title=Oxidants, oxidative stress and the biology of aging | journal=Nature | year=2000 | pages=239–47 | volume=408 | issue=6809 | pmid=11089981 | doi=10.1038/35041687}}</ref> In a similar set of reactions in plants, reactive oxygen species are also produced during [[photosynthesis]] under conditions of high light intensity.<ref>{{cite journal |author=Krieger-Liszkay A |title=Singlet oxygen production in photosynthesis |url=http://jxb.oxfordjournals.org/cgi/content/full/56/411/337 | doi = 10.1093/jxb/erh237 <!--Retrieved from url by DOI bot--> |journal=J Exp Bot |volume=56 |issue=411 |pages=337–46 |year=2005 |pmid=15310815}}</ref> This effect is partly offset by the involvement of [[carotenoid]]s in [[photoinhibition]], which involves these antioxidants reacting with over-reduced forms of the [[photosynthetic reaction centre]]s to prevent the production of reactive oxygen species.<ref>{{cite journal |author=Szabó I, Bergantino E, Giacometti G |title=Light and oxygenic photosynthesis: energy dissipation as a protection mechanism against photo-oxidation |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15995679 | doi = 10.1038/sj.embor.7400460 <!--Retrieved from url by DOI bot--> |journal=EMBO Rep |volume=6 |issue=7 |pages=629–34 |year=2005 |pmid=15995679}}</ref> ==Metabolites== ===Overview=== Antioxidants are classified into two broad divisions, depending on whether they are soluble in [[water]] ([[hydrophile|hydrophilic]]) or in lipids ([[hydrophobe|hydrophobic]]). In general, water-soluble antioxidants react with oxidants in the cell [[cytoplasm]] and the [[blood plasma]], while lipid-soluble antioxidants protect [[cell membrane]]s from lipid peroxidation.<ref name=Sies/> These compounds may be synthesized in the body or obtained from the diet.<ref name=Vertuani/> The different antioxidants are present at a wide range of concentrations in body fluids and tissues, with some such as glutathione or [[ubiquinone]] mostly present within cells, while others such as [[uric acid]] are more evenly distributed (see table below). The relative importance and interactions between these different antioxidants is a very complex question, with the various metabolites and enzyme systems having [[synergy|synergistic]] and interdependent effects on one another.<ref>{{cite journal |author=Chaudière J, Ferrari-Iliou R |title=Intracellular antioxidants: from chemical to biochemical mechanisms |journal=Food Chem Toxicol |volume=37 |issue=9–10 |pages=949 – 62 |year=1999 |pmid=10541450 |doi=10.1016/S0278-6915(99)00090-3}}</ref><ref>{{cite journal |author=Sies H |title=Strategies of antioxidant defense |journal=Eur J Biochem |volume=215 |issue=2 |pages=213 – 9 |year=1993 |pmid=7688300 |doi=10.1111/j.1432-1033.1993.tb18025.x}}</ref> The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system.<ref name=Vertuani/> The amount of protection provided by any one antioxidant will also depend on its concentration, its reactivity towards the particular reactive oxygen species being considered, and the status of the antioxidants with which it interacts.<ref name=Vertuani/> Some compounds contribute to antioxidant defense by [[chelation|chelating]] [[transition metal]]s and preventing them from catalyzing the production of free radicals in the cell. Particularly important is the ability to [[sequestration|sequester]] [[iron]], which is the function of [[iron-binding proteins]] such as [[transferrin]] and [[ferritin]].<ref>{{cite journal |author=Imlay J |title=Pathways of oxidative damage |journal=Annu Rev Microbiol |volume=57 |issue= |pages=395–418 |year=2003 |pmid=14527285 |doi=10.1146/annurev.micro.57.030502.090938}}</ref> [[Selenium]] and [[zinc]] are commonly referred to as ''antioxidant nutrients'', but these [[chemical element]]s have no antioxidant action themselves and are instead required for the activity of some antioxidant enzymes, as is discussed below. {| class="wikitable" style="margin-left: auto; margin-right: auto;" !Antioxidant metabolite !Solubility !Concentration in human serum (μM)<ref>{{cite journal |author=Ames B, Cathcart R, Schwiers E, Hochstein P |title=Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=349151&blobtype=pdf| journal=Proc Natl Acad Sci U S A |volume=78 |issue=11 |pages=6858 – 62 |year=1981 |pmid=6947260 |doi=10.1073/pnas.78.11.6858}}</ref> !Concentration in liver tissue (μmol/kg) |- |align="center" |[[Ascorbic acid]] (vitamin C) |align="center" |Water |align="center" |50 – 60<ref>{{cite journal |author=Khaw K, Woodhouse P |title=Interrelation of vitamin C, infection, haemostatic factors, and cardiovascular disease |url=http://www.bmj.com/cgi/content/full/310/6994/1559 |journal=BMJ |volume=310 |issue=6994 |pages=1559 – 63 |year=1995 |pmid=7787643}}</ref> |align="center" |260 (human)<ref name=Evelson>{{cite journal |author=Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi E |title=Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols |journal=Arch Biochem Biophys |volume=388 |issue=2 |pages=261 – 6 |year=2001 |pmid=11368163 |doi=10.1006/abbi.2001.2292}}</ref> |- |align="center" |[[Glutathione]] |align="center" |Water |align="center" |325 – 650<ref>{{cite journal |author=Chen C, Qu L, Li B, Xing L, Jia G, Wang T, Gao Y, Zhang P, Li M, Chen W, Chai Z |title=Increased oxidative DNA damage, as assessed by urinary 8-hydroxy-2'-deoxyguanosine concentrations, and serum redox status in persons exposed to mercury |url=http://www.clinchem.org/cgi/content/full/51/4/759 | doi = 10.1373/clinchem.2004.042093 <!--Retrieved from url by DOI bot--> |journal=Clin Chem |volume=51 |issue=4 |pages=759 – 67 |year=2005 |pmid=15695327}}</ref> |align="center" |6,400 (human)<ref name=Evelson/> |- |align="center" |[[Lipoic acid]] |align="center" |Water |align="center" |0.1 – 0.7<ref>{{cite journal |author=Teichert J, Preiss R |title=HPLC-methods for determination of lipoic acid and its reduced form in human plasma |journal=Int J Clin Pharmacol Ther Toxicol |volume=30 |issue=11 |pages=511 – 2 |year=1992 |pmid=1490813}}</ref> |align="center" |4 – 5 (rat)<ref>{{cite journal |author=Akiba S, Matsugo S, Packer L, Konishi T |title=Assay of protein-bound lipoic acid in tissues by a new enzymatic method |journal=Anal Biochem |volume=258 |issue=2 |pages=299 – 304 |year=1998 |pmid=9570844 |doi=10.1006/abio.1998.2615}}</ref> |- |align="center" |[[Uric acid]] |align="center" |Water |align="center" |200 – 400<ref>{{cite journal |author=Glantzounis G, Tsimoyiannis E, Kappas A, Galaris D |title=Uric acid and oxidative stress |journal=Curr Pharm Des |volume=11 |issue=32 |pages=4145 – 51 |year=2005 |pmid=16375736 |doi=10.2174/138161205774913255}}</ref> |align="center" |1,600 (human)<ref name=Evelson/> |- |align="center" |[[Carotene]]s |align="center" |Lipid |align="center" |[[carotene|β-carotene]]: 0.5 – 1<ref>{{cite journal |author=El-Sohemy A, Baylin A, Kabagambe E, Ascherio A, Spiegelman D, Campos H |title=Individual carotenoid concentrations in adipose tissue and plasma as biomarkers of dietary intake |journal=Am J Clin Nutr |volume=76 |issue=1 |pages=172 – 9 |year=2002 |pmid=12081831}}</ref> [[retinol]] (vitamin A): 1 – 3<ref name=Sowell>{{cite journal |author=Sowell A, Huff D, Yeager P, Caudill S, Gunter E |title=Retinol, alpha-tocopherol, lutein/zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, trans-beta-carotene, and four retinyl esters in serum determined simultaneously by reversed-phase HPLC with multiwavelength detection |url=http://www.clinchem.org/cgi/reprint/40/3/411.pdf?ijkey=12d7f1fb0a06f27c93b282ad4ea3435c0fb78f7e |journal=Clin Chem |volume=40 |issue=3 |pages=411 – 6 |year=1994 |pmid=8131277}}</ref> |align="center" |5 (human, total carotenoids)<ref>{{cite journal |author=Stahl W, Schwarz W, Sundquist A, Sies H |title=cis-trans isomers of lycopene and beta-carotene in human serum and tissues |journal=Arch Biochem Biophys |volume=294 |issue=1 |pages=173 – 7 |year=1992 |pmid=1550343 |doi=10.1016/0003-9861(92)90153-N}}</ref> |- |align="center" |[[tocopherol|α-tocopherol]] (vitamin E) |align="center" |Lipid |align="center" |10 – 40<ref name=Sowell/> |align="center" |50 (human)<ref name=Evelson/> |- |align="center" |[[Coenzyme Q|Ubiquinol]] (coenzyme Q) |align="center" |Lipid |align="center" |5<ref>{{cite journal |author=Zita C, Overvad K, Mortensen S, Sindberg C, Moesgaard S, Hunter D |title=Serum coenzyme Q10 concentrations in healthy men supplemented with {{nowrap|30 mg}} or {{nowrap|100 mg}} coenzyme Q10 for two months in a randomised controlled study |journal=Biofactors |volume=18 |issue=1 – 4 |pages=185 – 93 |year=2003 |pmid=14695934}}</ref> |align="center" |200 (human)<ref name=Turunen>{{cite journal |author=Turunen M, Olsson J, Dallner G |title=Metabolism and function of coenzyme Q |journal=Biochim Biophys Acta |volume=1660 |issue=1 – 2 |pages=171 – 99 |year=2004 |pmid=14757233 |doi=10.1016/j.bbamem.2003.11.012}}</ref> |} ===Ascorbic acid=== Ascorbic acid or "vitamin C" is a [[monosaccharide]] antioxidant found in both animals and plants. As it cannot be synthesised in humans and must be obtained from the diet, it is a vitamin.<ref>{{cite journal |author=Smirnoff N |title=L-ascorbic acid biosynthesis |journal=Vitam Horm |volume=61 |issue= |pages=241 – 66 |year=2001 |pmid=11153268}}</ref> Most other animals are able to produce this compound in their bodies and do not require it in their diets.<ref>{{cite journal |author=Linster CL, Van Schaftingen E |title=Vitamin C. Biosynthesis, recycling and degradation in mammals |journal=FEBS J. |volume=274 |issue=1 |pages=1–22 |year=2007 |pmid=17222174}}</ref> In cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by [[protein disulfide isomerase]] and [[glutaredoxin]]s.<ref name=MeisterA>{{cite journal |author=Meister A |title=Glutathione-ascorbic acid antioxidant system in animals |journal=J Biol Chem |volume=269 |issue=13 |pages=9397 – 400 |year=1994 |pmid=8144521}}</ref><ref>{{cite journal |author=Wells W, Xu D, Yang Y, Rocque P |title=Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity |url=http://www.jbc.org/cgi/reprint/265/26/15361 |journal=J Biol Chem |volume=265 |issue=26 |pages=15361 – 4 |year=1990 |pmid=2394726}}</ref> Ascorbic acid is a reducing agent and can reduce and thereby neutralize reactive oxygen species such as hydrogen peroxide.<ref>{{cite journal |author=Padayatty S, Katz A, Wang Y, Eck P, Kwon O, Lee J, Chen S, Corpe C, Dutta A, Dutta S, Levine M |title=Vitamin C as an antioxidant: evaluation of its role in disease prevention |url=http://www.jacn.org/cgi/content/full/22/1/18 |journal=J Am Coll Nutr |volume=22 |issue=1 |pages=18 – 35 |year=2003 |pmid=12569111}}</ref> In addition to its direct antioxidant effects, ascorbic acid is also a [[substrate (biochemistry)|substrate]] for the antioxidant enzyme [[ascorbate peroxidase]], a function that is particularly important in stress resistance in plants.<ref>{{cite journal |author=Shigeoka S, Ishikawa T, Tamoi M, Miyagawa Y, Takeda T, Yabuta Y, Yoshimura K |title=Regulation and function of ascorbate peroxidase isoenzymes |url=http://jxb.oxfordjournals.org/cgi/content/full/53/372/1305 |journal=J Exp Bot |volume=53 |issue=372 |pages=1305 – 19 |year=2002 |pmid=11997377 |doi=10.1093/jexbot/53.372.1305}}</ref> ===Glutathione=== [[Image:Lipid peroxidation.svg|thumb|350px|right|The [[Radical (chemistry)|free radical]] mechanism of lipid peroxidation.]] Glutathione is a [[cysteine]]-containing [[peptide]] found in most forms of aerobic life.<ref name=MeisterB>{{cite journal |author=Meister A, Anderson M |title=Glutathione |journal=Annu Rev Biochem |volume=52 |pages=711 – 60 |year=1983 |pmid=6137189 |doi=10.1146/annurev.bi.52.070183.003431}}</ref> It is not required in the diet and is instead synthesized in cells from its constituent [[amino acid]]s.<ref>{{cite journal |author=Meister A |title=Glutathione metabolism and its selective modification |url=http://www.jbc.org/cgi/reprint/263/33/17205.pdf |journal=J Biol Chem |volume=263 |issue=33 |pages=17205 – 8 |year=1988 |pmid=3053703}}</ref> Glutathione has antioxidant properties since the [[thiol]] group in its [[cysteine]] [[moiety]] is a reducing agent and can be reversibly oxidized and reduced. In cells, glutathione is maintained in the reduced form by the enzyme [[glutathione reductase]] and in turn reduces other metabolites and enzyme systems as well as reacting directly with oxidants.<ref name=MeisterA/> Due to its high concentration and its central role in maintaining the cell's redox state, glutathione is one of the most important cellular antioxidants.<ref name=MeisterB/> ===Melatonin=== [[Melatonin]] is a powerful antioxidant that can easily cross cell membranes and the [[blood-brain barrier]].<ref>{{cite journal |author=Reiter RJ, Carneiro RC, Oh CS |title=Melatonin in relation to cellular antioxidative defense mechanisms |journal=Horm. Metab. Res. |volume=29 |issue=8 |pages=363–72 |year=1997 |pmid=9288572}}</ref> Unlike other antioxidants, melatonin does not undergo [[redox cycling]], which is the ability of a molecule to undergo repeated [[reduction (chemistry)|reduction]] and [[oxidation]]. Redox cycling may allow other antioxidants (such as vitamin C) to act as [[pro-oxidant]]s and promote free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.<ref name="Tan2000">{{cite journal |author=Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR |title=Significance of melatonin in antioxidative defense system: reactions and products |journal=Biological signals and receptors |volume=9 |issue=3–4 |pages=137–59 |year=2000 |pmid=10899700 |doi=10.1159/000014635}}</ref> ===Tocopherols and tocotrienols (vitamin E)=== [[Vitamin E]] is the collective name for a set of eight related tocopherols and [[tocotrienol]]s, which are fat-soluble vitamins with antioxidant properties.<ref name=Herrera>{{cite journal |author=Herrera E, Barbas C |title=Vitamin E: action, metabolism and perspectives |journal=J Physiol Biochem |volume=57 |issue=2 |pages=43 – 56 |year=2001 |pmid=11579997}}</ref><ref>{{cite journal |author=Packer L, Weber SU, Rimbach G |title=Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling |journal=J. Nutr. |volume=131 |issue=2 |pages=369S–73S |year=2001 |pmid=11160563 |url=http://jn.nutrition.org/cgi/content/full/131/2/369S}}</ref> Of these, α-tocopherol has been most studied as it has the highest [[bioavailability]], with the body preferentially absorbing and metabolising this form.<ref name=Brigelius>{{cite journal |author=Brigelius-Flohé R, Traber M |title=Vitamin E: function and metabolism |url=http://www.fasebj.org/cgi/content/full/13/10/1145 |journal=FASEB J |volume=13 |issue=10 |pages=1145 – 55 |year=1999 |pmid=10385606}}</ref> It has been claimed that the α-tocopherol form is the most important lipid-soluble antioxidant, and that it protects membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction.<ref name=Herrera/><ref>{{cite journal |author=Traber MG, Atkinson J |title=Vitamin E, antioxidant and nothing more |journal=Free Radic. Biol. Med. |volume=43 |issue=1 |pages=4–15 |year=2007 |pmid=17561088 |doi=10.1016/j.freeradbiomed.2007.03.024}}</ref> This removes the free radical intermediates and prevents the propagation reaction from continuing. This reaction produces oxidised α-tocopheroxyl radicals that can be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol.<ref>{{cite journal |author=Wang X, Quinn P |title=Vitamin E and its function in membranes |journal=Prog Lipid Res |volume=38 |issue=4 |pages=309 – 36 |year=1999 |pmid=10793887 |doi=10.1016/S0163-7827(99)00008-9}}</ref> However, the roles and importance of the various forms of vitamin E are presently unclear,<ref>{{cite journal |author=Brigelius-Flohé R, Davies KJ |title=Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food? Comments on the two accompanying papers: "Molecular mechanism of alpha-tocopherol action" by A. Azzi and "Vitamin E, antioxidant and nothing more" by M. Traber and J. Atkinson |journal=Free Radic. Biol. Med. |volume=43 |issue=1 |pages=2–3 |year=2007 |pmid=17561087}}</ref><ref>{{cite journal |author=Atkinson J, Epand RF, Epand RM |title=Tocopherols and tocotrienols in membranes: A critical review |journal=Free Radic. Biol. Med. |volume=44 |issue=5 |pages=739–764 |year=2007 |pmid=18160049 |doi=10.1016/j.freeradbiomed.2007.11.010}}</ref> and it has even been suggested that the most important function of α-tocopherol is as a [[cell signaling|signaling molecule]], with this molecule having no significant role in antioxidant metabolism.<ref name=Azzi>{{cite journal |author=Azzi A |title=Molecular mechanism of alpha-tocopherol action |journal=Free Radic. Biol. Med. |volume=43 |issue=1 |pages=16–21 |year=2007 |pmid=17561089 |doi=10.1016/j.freeradbiomed.2007.03.013}}</ref><ref>{{cite journal |author=Zingg JM, Azzi A |title=Non-antioxidant activities of vitamin E |journal=Curr. Med. Chem. |volume=11 |issue=9 |pages=1113–33 |year=2004 |pmid=15134510}}</ref> The functions of the other forms of vitamin E are even less well-understood, although γ-tocopherol is a [[nucleophile]] that may react with [[electrophile|electrophilic]] mutagens,<ref name=Brigelius/> and tocotrienols may be important in protecting [[neuron]]s from damage.<ref>{{cite journal |author=Sen C, Khanna S, Roy S |title=Tocotrienols: Vitamin E beyond tocopherols |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1790869&blobtype=pdf |journal=Life Sci |volume=78 |issue=18 |pages=2088 – 98 |year=2006 |pmid=16458936 |doi=10.1016/j.lfs.2005.12.001}}</ref> ==Pro-oxidant activities== {{further|[[Pro-oxidant]]}} Antioxidants that are reducing agents can also act as pro-oxidants. For example, vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,<ref>{{cite journal |author=Duarte TL, Lunec J |title=Review: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C |journal=Free Radic. Res. |volume=39 |issue=7 |pages=671–86 |year=2005 |pmid=16036346}}</ref> however, it will also reduce metal ions that generate free radicals through the [[Fenton's reagent|Fenton reaction]].<ref name=Carr>{{cite journal |author=Carr A, Frei B |title=Does vitamin C act as a pro-oxidant under physiological conditions? |url=http://www.fasebj.org/cgi/content/full/13/9/1007 |journal=FASEB J. |volume=13 |issue=9 |pages=1007–24 |year=1999 |pmid=10336883}}</ref><ref>{{cite journal |author=Stohs SJ, Bagchi D |title=Oxidative mechanisms in the toxicity of metal ions |journal=Free Radic. Biol. Med. |volume=18 |issue=2 |pages=321–36 |year=1995 |pmid=7744317 |doi=10.1016/0891-5849(94)00159-H}}</ref> :2 Fe<sup>3+</sup> + Ascorbate → 2 Fe<sup>2+</sup> + Dehydroascorbate ::2 Fe<sup>2+</sup> + 2 H<sub>2</sub>O<sub>2</sub> → 2 Fe<sup>3+</sup> + 2 OH'''·''' + 2 OH<sup>−</sup> The relative importance of the antioxidant and pro-oxidant activities of antioxidants are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body.<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 |pmid=15892631 |doi=10.2174/0929867053764635}}</ref><ref name=Carr/> However, fewer data are available for other dietary antioxidants, such as vitamin E.<ref>{{cite journal |author=Schneider C |title=Chemistry and biology of vitamin E |journal=Mol Nutr Food Res |volume=49 |issue=1 |pages=7–30 |year=2005 |pmid=15580660 |doi=10.1002/mnfr.200400049}}</ref> ==Enzyme systems== [[Image:Antioxidant pathway.svg|thumb|right|400px|Enzymatic pathway for detoxification of reactive oxygen species.]] ===Overview=== As with the chemical antioxidants, cells are protected against oxidative stress by an interacting network of antioxidant enzymes.<ref name=Sies/><ref name=Davies/> Here, the superoxide released by processes such as oxidative phosphorylation is first converted to hydrogen peroxide and then further reduced to give water. This detoxification pathway is the result of multiple enzymes, with superoxide dismutases catalysing the first step and then catalases and various peroxidases removing hydrogen peroxide. As with antioxidant metabolites, the contributions of these enzymes to the antioxidant defenses of a cell can be hard to separate from one another, but the generation of [[Genetically modified organism|transgenic mice]] lacking just one antioxidant enzyme can be informative.<ref name=Magnenat>{{cite journal |author=Ho Y, Magnenat J, Gargano M, Cao J |title=The nature of antioxidant defense mechanisms: a lesson from transgenic studies |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1533365&blobtype=pdf |journal=Environ Health Perspect |volume=106 Suppl 5 |issue= |pages=1219–28 |year=9788901 |pmid=9788901}}</ref> ===Superoxide dismutase, catalase and peroxiredoxins=== [[Superoxide dismutase]]s (SODs) are a class of closely related enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide.<ref>{{cite journal |author=Zelko I, Mariani T, Folz R |title=Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression |journal=Free Radic Biol Med |volume=33 |issue=3 |pages=337–49 |year=2002 |pmid=12126755 |doi=10.1016/S0891-5849(02)00905-X}}</ref><ref name=Bannister>{{cite journal |author=Bannister J, Bannister W, Rotilio G |title=Aspects of the structure, function, and applications of superoxide dismutase |journal=CRC Crit Rev Biochem |volume=22 |issue=2 |pages=111–80 |year=1987 |pmid=3315461 |doi=10.3109/10409238709083738}}</ref> SOD enzymes are present in almost all aerobic cells and in extracellular fluids.<ref>{{cite journal |author=Johnson F, Giulivi C |title=Superoxide dismutases and their impact upon human health |journal=Mol Aspects Med |volume=26 |issue=4–5 |pages=340–52 |year=2005 |pmid=16099495 |doi=10.1016/j.mam.2005.07.006}}</ref> Superoxide dismutase enzymes contain metal ion cofactors that, depending on the isozyme, can be [[copper]], zinc, [[manganese]] or [[iron]]. In humans, the copper/zinc SOD is present in the [[cytosol]], while manganese SOD is present in the [[mitochondrion]].<ref name=Bannister/> There also exists a third form of SOD in [[extracellular fluid]]s, which contains copper and zinc in its active sites.<ref>{{cite journal |author=Nozik-Grayck E, Suliman H, Piantadosi C |title=Extracellular superoxide dismutase |journal=Int J Biochem Cell Biol |volume=37 |issue=12 |pages=2466–71 |year=2005 |pmid=16087389 |doi=10.1016/j.biocel.2005.06.012}}</ref> The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth.<ref>{{cite journal |author=Melov S, Schneider J, Day B, Hinerfeld D, Coskun P, Mirra S, Crapo J, Wallace D |title=A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase |journal=Nat Genet |volume=18 |issue=2 |pages=159–63 |year=1998 |pmid=9462746 |doi=10.1038/ng0298-159}}</ref> In contrast, the mice lacking copper/zinc SOD are viable but have lowered fertility, while mice without the extracellular SOD have minimal defects.<ref name=Magnenat/><ref>{{cite journal |author=Reaume A, Elliott J, Hoffman E, Kowall N, Ferrante R, Siwek D, Wilcox H, Flood D, Beal M, Brown R, Scott R, Snider W |title=Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury |journal=Nat Genet |volume=13 |issue=1 |pages=43–7 |year=1996 |pmid=8673102 |doi=10.1038/ng0596-43}}</ref> In plants, SOD isozymes are present in the cytosol and mitochondria, with an iron SOD found in [[chloroplast]]s that is absent from [[vertebrate]]s and [[yeast]].<ref>{{cite journal |author=Van Camp W, Inzé D, Van Montagu M |title=The regulation and function of tobacco superoxide dismutases |journal=Free Radic Biol Med |volume=23 |issue=3 |pages=515–20 |year=1997 |pmid=9214590 |doi=10.1016/S0891-5849(97)00112-3}}</ref> [[Catalase]]s are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor.<ref>{{cite journal |author=Chelikani P, Fita I, Loewen P |title=Diversity of structures and properties among catalases |journal=Cell Mol Life Sci |volume=61 |issue=2 |pages=192–208 |year=2004 |pmid=14745498 |doi=10.1007/s00018-003-3206-5}}</ref><ref>{{cite journal |author=Zámocký M, Koller F |title=Understanding the structure and function of catalases: clues from molecular evolution and ''in vitro'' mutagenesis |journal=Prog Biophys Mol Biol |volume=72 |issue=1 |pages=19–66 |year=1999 |pmid=10446501 |doi=10.1016/S0079-6107(98)00058-3}}</ref> This protein is localized to [[peroxisome]]s in most [[eukaryote|eukaryotic]] cells.<ref>{{cite journal |author=del Río L, Sandalio L, Palma J, Bueno P, Corpas F |title=Metabolism of oxygen radicals in peroxisomes and cellular implications |journal=Free Radic Biol Med |volume=13 |issue=5 |pages=557–80 |year=1992 |pmid=1334030 |doi=10.1016/0891-5849(92)90150-F}}</ref> Catalase is an unusual enzyme since, although hydrogen peroxide is its only substrate, it follows a [[enzyme kinetics|ping-pong mechanism]]. Here, its cofactor is oxidised by one molecule of hydrogen peroxide and then regenerated by transferring the bound oxygen to a second molecule of substrate.<ref>{{cite journal |author=Hiner A, Raven E, Thorneley R, García-Cánovas F, Rodríguez-López J |title=Mechanisms of compound I formation in heme peroxidases |journal=J Inorg Biochem |volume=91 |issue=1 |pages=27–34 |year=2002 |pmid=12121759 |doi=10.1016/S0162-0134(02)00390-2}}</ref> Despite its apparent importance in hydrogen peroxide removal, humans with genetic deficiency of catalase — "[[acatalasemia]]" — or mice genetically engineered to lack catalase completely, suffer few ill effects.<ref>{{cite journal |author=Mueller S, Riedel H, Stremmel W |title=Direct evidence for catalase as the predominant H2O2 -removing enzyme in human erythrocytes |url=http://www.bloodjournal.org/cgi/content/full/90/12/4973 |journal=Blood |volume=90 |issue=12 |pages=4973–8 |year=1997 |pmid=9389716}}</ref><ref>{{cite journal |author=Ogata M |title=Acatalasemia |journal=Hum Genet |volume=86 |issue=4 |pages=331–40 |year=1991 |pmid=1999334 |doi=10.1007/BF00201829}}</ref> [[Image:Peroxiredoxin.png|thumb|left|300px|[[Quaternary structure|Decameric]] structure of AhpC, a [[bacterial]] 2-cysteine [[peroxiredoxin]] from ''[[Salmonella enterica|Salmonella typhimurium]]''.<ref>{{cite journal |author=Parsonage D, Youngblood D, Sarma G, Wood Z, Karplus P, Poole L |title=Analysis of the link between enzymatic activity and oligomeric state in AhpC, a bacterial peroxiredoxin |journal=Biochemistry |volume=44 |issue=31 |pages=10583–92 |year=2005 |pmid=16060667 |doi=10.1021/bi050448i}} [http://www.rcsb.org/pdb/explore.do?structureId=1YEX PDB 1YEX]</ref>]] [[Peroxiredoxin]]s are peroxidases that catalyze the reduction of hydrogen peroxide, [[organic peroxide|organic hydroperoxide]]s, as well as [[peroxynitrite]].<ref>{{cite journal |author=Rhee S, Chae H, Kim K |title=Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling |journal=Free Radic Biol Med |volume=38 |issue=12 |pages=1543–52 |year=2005 |pmid=15917183 |doi=10.1016/j.freeradbiomed.2005.02.026}}</ref> They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins.<ref>{{cite journal |author=Wood Z, Schröder E, Robin Harris J, Poole L |title=Structure, mechanism and regulation of peroxiredoxins |journal=Trends Biochem Sci |volume=28 |issue=1 |pages=32–40 |year=2003 |pmid=12517450 |doi=10.1016/S0968-0004(02)00003-8}}</ref> These enzymes share the same basic catalytic mechanism, in which a redox-active cysteine (the peroxidatic cysteine) in the active site is oxidized to a [[sulfenic acid]] by the peroxide substrate.<ref>{{cite journal |author=Claiborne A, Yeh J, Mallett T, Luba J, Crane E, Charrier V, Parsonage D |title=Protein-sulfenic acids: diverse roles for an unlikely player in enzyme catalysis and redox regulation |journal=Biochemistry |volume=38 |issue=47 |pages=15407–16 |year=1999 |pmid=10569923 |doi=10.1021/bi992025k}}</ref> Peroxiredoxins seem to be important in antioxidant metabolism, as mice lacking peroxiredoxin 1 or 2 have shortened lifespan and suffer from [[hemolytic anaemia]], while plants use peroxiredoxins to remove hydrogen peroxide generated in chloroplasts.<ref>{{cite journal |author=Neumann C, Krause D, Carman C, Das S, Dubey D, Abraham J, Bronson R, Fujiwara Y, Orkin S, Van Etten R |title=Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression |journal=Nature |volume=424 |issue=6948 |pages=561–5 |year=2003 |pmid=12891360 |doi=10.1038/nature01819}}</ref><ref>{{cite journal |author=Lee T, Kim S, Yu S, Kim S, Park D, Moon H, Dho S, Kwon K, Kwon H, Han Y, Jeong S, Kang S, Shin H, Lee K, Rhee S, Yu D |title=Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice |url=http://www.bloodjournal.org/cgi/content/full/101/12/5033 | doi = 10.1182/blood-2002-08-2548 <!--Retrieved from url by DOI bot--> |journal=Blood |volume=101 |issue=12 |pages=5033–8 |year=2003 |pmid=12586629}}</ref><ref>{{cite journal |author=Dietz K, Jacob S, Oelze M, Laxa M, Tognetti V, de Miranda S, Baier M, Finkemeier I |title=The function of peroxiredoxins in plant organelle redox metabolism |journal=J Exp Bot |volume=57 |issue=8 |pages=1697–709 |year=2006 |pmid=16606633 |doi=10.1093/jxb/erj160}}</ref> ===Thioredoxin and glutathione systems=== The [[thioredoxin]] system contains the 12-k[[atomic mass unit|Da]] protein thioredoxin and its companion [[thioredoxin reductase]].<ref>{{cite journal | author=Nordberg J, Arner ES | title=Reactive oxygen species, antioxidants, and the mammalian thioredoxin system | journal=Free Radic Biol Med | year=2001 | pages=1287–312 | volume=31 | issue=11 | pmid=11728801 | doi=10.1016/S0891-5849(01)00724-9}}</ref> Proteins related to thioredoxin are present in all sequenced organisms, with plants such as ''[[Arabidopsis thaliana]]'' having a particularly great diversity of isoforms.<ref>{{cite journal |author=Vieira Dos Santos C, Rey P |title=Plant thioredoxins are key actors in the oxidative stress response |journal=Trends Plant Sci |volume=11 |issue=7 |pages=329–34 |year=2006 |pmid=16782394 |doi=10.1016/j.tplants.2006.05.005}}</ref> The active site of thioredoxin consists of two [[vicinal (chemistry)|neighboring]] cysteines, as part of a highly-conserved CXXC [[sequence motif|motif]], that can cycle between an active dithiol form (reduced) and an oxidized [[disulfide]] form. In its active state, thioredoxin acts as an efficient reducing agent, scavenging reactive oxygen species and maintaining other proteins in their reduced state.<ref>{{cite journal |author=Arnér E, Holmgren A |title=Physiological functions of thioredoxin and thioredoxin reductase |url=http://www.blackwell-synergy.com/doi/full/10.1046/j.1432-1327.2000.01701.x | doi = 10.1046/j.1432-1327.2000.01701.x <!--Retrieved from url by DOI bot--> |journal=Eur J Biochem |volume=267 |issue=20 |pages=6102–9 |year=2000 |pmid=11012661}}</ref> After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using [[NADPH]] as an electron donor.<ref>{{cite journal |author=Mustacich D, Powis G |title=Thioredoxin reductase |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10657232 |journal=Biochem J |volume=346 Pt 1 |issue= |pages=1–8 |year=2000 |pmid=10657232 |doi=10.1042/0264-6021:3460001}}</ref> The glutathione system includes glutathione, glutathione reductase, [[glutathione peroxidase]]s and glutathione ''S''-transferases.<ref name=MeisterB/> This system is found in animals, plants and microorganisms.<ref>{{cite journal |author=Creissen G, Broadbent P, Stevens R, Wellburn A, Mullineaux P |title=Manipulation of glutathione metabolism in transgenic plants |journal=Biochem Soc Trans |volume=24 |issue=2 |pages=465–9 |year=1996 |pmid=8736785}}</ref><ref name=MeisterB/> Glutathione peroxidase is an enzyme containing four [[selenium]]-[[cofactor]]s that catalyzes the breakdown of hydrogen peroxide and organic hydroperoxides. There are at least four different glutathione peroxidase [[isozyme]]s in animals.<ref>{{cite journal |author=Brigelius-Flohé R |title=Tissue-specific functions of individual glutathione peroxidases |journal=Free Radic Biol Med |volume=27 |issue=9–10 |pages=951–65 |year=1999 |pmid=10569628 |doi=10.1016/S0891-5849(99)00173-2}}</ref> Glutathione peroxidase 1 is the most abundant and is a very efficient scavenger of hydrogen peroxide, while glutathione peroxidase 4 is most active with lipid hydroperoxides. Surprisingly, glutathione peroxidase 1 is dispensable, as mice lacking this enzyme have normal lifespans,<ref>{{cite journal |author=Ho Y, Magnenat J, Bronson R, Cao J, Gargano M, Sugawara M, Funk C |title=Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia |url=http://www.jbc.org/cgi/content/full/272/26/16644 |journal=J Biol Chem |volume=272 |issue=26 |pages=16644–51 |year=1997 |pmid=9195979 |doi=10.1074/jbc.272.26.16644}}</ref> but they are hypersensitive to induced oxidative stress.<ref>{{cite journal |author=de Haan J, Bladier C, Griffiths P, Kelner M, O'Shea R, Cheung N, Bronson R, Silvestro M, Wild S, Zheng S, Beart P, Hertzog P, Kola I |title=Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide |url=http://www.jbc.org/cgi/content/full/273/35/22528 |journal=J Biol Chem |volume=273 |issue=35 |pages=22528–36 |year=1998 |pmid=9712879 |doi=10.1074/jbc.273.35.22528}}</ref> In addition, the [[glutathione S-transferase|glutathione ''S''-transferases]] are another class of glutathione-dependent antioxidant enzymes that show high activity with lipid peroxides.<ref>{{cite journal |author=Sharma R, Yang Y, Sharma A, Awasthi S, Awasthi Y |title=Antioxidant role of glutathione S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis |journal=Antioxid Redox Signal |volume=6 |issue=2 |pages=289–300 |year=2004 |pmid=15025930 |doi=10.1089/152308604322899350}}</ref> These enzymes are at particularly high levels in the liver and also serve in [[detoxification]] metabolism.<ref>{{cite journal |author=Hayes J, Flanagan J, Jowsey I |title=Glutathione transferases |journal=Annu Rev Pharmacol Toxicol |volume=45 |issue= |pages=51–88 |year=2005 |pmid=15822171 |doi=10.1146/annurev.pharmtox.45.120403.095857}}</ref> ==Oxidative stress in disease== {{further|[[Pathology]], [[Free-radical theory|Free-radical theory of aging]]}} Oxidative stress is thought to contribute to the development of a wide range of diseases including [[Alzheimer's disease]],<ref>{{cite journal |author=Christen Y |title=Oxidative stress and Alzheimer disease |url=http://www.ajcn.org/cgi/content/full/71/2/621s |journal=Am J Clin Nutr |volume=71 |issue=2 |pages=621S–629S |year=2000 |pmid=10681270}}</ref><ref>{{cite journal |author=Nunomura A, Castellani R, Zhu X, Moreira P, Perry G, Smith M |title=Involvement of oxidative stress in Alzheimer disease |journal=J Neuropathol Exp Neurol |volume=65 |issue=7 |pages=631–41 |year=2006 |pmid=16825950 |doi=10.1097/01.jnen.0000228136.58062.bf}}</ref> [[Parkinson's disease]],<ref>{{cite journal |author=Wood-Kaczmar A, Gandhi S, Wood N |title=Understanding the molecular causes of Parkinson's disease |journal=Trends Mol Med |volume=12 |issue=11 |pages=521–8 |year=2006 |pmid=17027339 |doi=10.1016/j.molmed.2006.09.007}}</ref> the pathologies caused by [[diabetes]],<ref>{{cite journal |author=Davì G, Falco A, Patrono C |title=Lipid peroxidation in diabetes mellitus |journal=Antioxid Redox Signal |volume=7 |issue=1–2 |pages=256–68 |year=2005 |pmid=15650413 |doi=10.1089/ars.2005.7.256}}</ref><ref>{{cite journal |author=Giugliano D, Ceriello A, Paolisso G |title=Oxidative stress and diabetic vascular complications |journal=Diabetes Care |volume=19 |issue=3 |pages=257–67 |year=1996 |pmid=8742574 |doi=10.2337/diacare.19.3.257}}</ref> [[rheumatoid arthritis]],<ref>{{cite journal |author=Hitchon C, El-Gabalawy H |title=Oxidation in rheumatoid arthritis |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15535839 | doi = 10.1186/ar1447 <!--Retrieved from url by DOI bot--> |journal=Arthritis Res Ther |volume=6 |issue=6 |pages=265–78 |year=2004 |pmid=15535839}}</ref> and [[neurodegeneration]] in [[motor neurone disease]]s.<ref>{{cite journal |author=Cookson M, Shaw P |title=Oxidative stress and motor neurone disease |journal=Brain Pathol |volume=9 |issue=1 |pages=165–86 |year=1999 |pmid=9989458}}</ref> In many of these cases, it is unclear if oxidants trigger the disease, or if they are produced as a consequence of the disease and cause the disease [[symptom]]s;<ref name = "emfafb"/> as a plausible alternative, a neurodegenerative disease might result from defective [[axoplasmic transport|axonal transport]] of mitochondria, which carry out oxidation reactions. One case in which this link is particularly well-understood is the role of oxidative stress in [[cardiovascular disease]]. Here, [[low density lipoprotein]] (LDL) oxidation appears to trigger the process of [[atherosclerosis#Atherogenesis|atherogenesis]], which results in [[atherosclerosis]], and finally cardiovascular disease.<ref>{{cite journal |author=Van Gaal L, Mertens I, De Block C |title=Mechanisms linking obesity with cardiovascular disease |journal=Nature |volume=444 |issue=7121 |pages=875–80 |year=2006 |pmid=17167476 |doi=10.1038/nature05487}}</ref><ref>{{cite journal |author=Aviram M |title=Review of human studies on oxidative damage and antioxidant protection related to cardiovascular diseases |journal=Free Radic Res |volume=33 Suppl |issue= |pages=S85–97 |year=2000 |pmid=11191279}}</ref> A [[Calorie restriction|low calorie diet]] extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress.<ref>{{cite journal | doi=10.1073/pnas.0510452103 | author=G. López-Lluch, N. Hunt, B. Jones, M. Zhu, H. Jamieson, S. Hilmer, M. V. Cascajo, J. Allard, D. K. Ingram, P. Navas, and R. de Cabo | title=Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency | journal=Proc Natl Acad Sci U S A |year=2006 | volume=103 | issue=6 | pages=1768 – 1773 | pmid=16446459}}</ref> While there is good evidence to support the role of oxidative stress in aging in model organisms such as ''[[Drosophila melanogaster]]'' and ''[[Caenorhabditis elegans]]'',<ref>{{cite journal |author=Larsen P |title=Aging and resistance to oxidative damage in Caenorhabditis elegans |url=http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?itool=AbstractPlus-def&PrId=3494&uid=8415630&db=pubmed&url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8415630 |journal=Proc Natl Acad Sci U S A |volume=90 |issue=19 |pages=8905–9 |year=1993 |pmid=8415630 |doi=10.1073/pnas.90.19.8905}}</ref><ref>{{cite journal |author=Helfand S, 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> the evidence in mammals is less clear.<ref name = "hdanrt">{{cite journal |author=Sohal R, Mockett R, Orr W |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=10.1016/S0891-5849(02)00886-9}}</ref><ref>{{cite journal |author=Sohal R |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=10.1016/S0891-5849(02)00856-0}}</ref><ref>{{cite journal |author=Rattan S |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> Diets high in fruit and vegetables, which are high in antioxidants, promote health and reduce the effects of aging, however antioxidant vitamin supplementation has no detectable effect on the aging process, so the effects of fruit and vegetables may be unrelated to their antioxidant contents.<ref>{{cite journal |author=Thomas D |title=Vitamins in health and aging |journal=Clin Geriatr Med |volume=20 |issue=2 |pages=259–74 |year=2004 |pmid=15182881 |doi=10.1016/j.cger.2004.02.001}}</ref><ref>{{cite journal |author=Ward J |title=Should antioxidant vitamins be routinely recommended for older people? |journal=Drugs Aging |volume=12 |issue=3 |pages=169–75 |year=1998 |pmid=9534018 |doi=10.2165/00002512-199812030-00001}}</ref> One reason for this might be the fact that consuming antioxidant molecules such as polyphenols and vitamin E will produce changes in other parts of metabolism, so it may be these other non-antioxidant effects that are the real reason they are important in human nutrition.<ref>{{cite journal |author=Aggarwal BB, Shishodia S |title=Molecular targets of dietary agents for prevention and therapy of cancer |journal=Biochem. Pharmacol. |volume=71 |issue=10 |pages=1397–421 |year=2006 |pmid=16563357 |doi=10.1016/j.bcp.2006.02.009}}</ref><ref name=Azzi/> ==Health effects== ===Disease treatment=== The [[brain]] is uniquely vulnerable to oxidative injury, due to its high metabolic rate and elevated levels of polyunsaturated lipids, the target of lipid peroxidation.<ref>{{cite journal |author=Reiter R |title=Oxidative processes and antioxidative defense mechanisms in the aging brain |url=http://www.fasebj.org/cgi/reprint/9/7/526.pdf |journal=FASEB J |volume=9 |issue=7 |pages=526–33 |year=1995 |pmid=7737461}}</ref> Consequently, antioxidants are commonly used as [[medication]]s to treat various forms of brain injury. Here, superoxide dismutase mimetics,<ref>{{cite journal |author=Warner D, Sheng H, Batinić-Haberle I |title=Oxidants, antioxidants and the ischemic brain |url=http://jeb.biologists.org/cgi/content/full/207/18/3221 |journal=J Exp Biol |volume=207 |issue=Pt 18 |pages=3221–31 |year=2004 |pmid=15299043 |doi=10.1242/jeb.01022}}</ref> [[sodium thiopental]] and [[propofol]] are used to treat [[reperfusion injury]] and [[traumatic brain injury]],<ref>{{cite journal |author=Wilson J, Gelb A |title=Free radicals, antioxidants, and neurologic injury: possible relationship to cerebral protection by anesthetics |journal=J Neurosurg Anesthesiol |volume=14 |issue=1 |pages=66–79 |year=2002 |pmid=11773828 |doi=10.1097/00008506-200201000-00014}}</ref> while the experimental drug [[NXY-059]]<ref>{{cite journal |author=Lees K, Davalos A, Davis S, Diener H, Grotta J, Lyden P, Shuaib A, Ashwood T, Hardemark H, Wasiewski W, Emeribe U, Zivin J |title=Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial |journal=Stroke |volume=37 |issue=12 |pages=2970–8 |year=2006 |pmid=17068304 |doi=10.1161/01.STR.0000249410.91473.44}}</ref><ref>{{cite journal |author=Lees K, Zivin J, Ashwood T, Davalos A, Davis S, Diener H, Grotta J, Lyden P, Shuaib A, Hårdemark H, Wasiewski W |title=NXY-059 for acute ischemic stroke |journal=N Engl J Med |volume=354 |issue=6 |pages=588–600 |year=2006 |pmid=16467546 |doi=10.1056/NEJMoa052980}}</ref> and [[ebselen]]<ref>{{cite journal |author=Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H |title=Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group |url=http://stroke.ahajournals.org/cgi/content/full/29/1/12 |journal=Stroke |volume=29 |issue=1 |pages=12–7 |year=1998 |pmid=9445321}}</ref> are being applied in the treatment of stroke. These compounds appear to prevent oxidative stress in neurons and prevent [[apoptosis]] and neurological damage. Antioxidants are also being investigated as possible treatments for neurodegenerative diseases such as [[Alzheimers|Alzheimer's disease]], [[Parkinsons|Parkinson's disease]], and [[amyotrophic lateral sclerosis]],<ref>{{cite journal |author=Di Matteo V, Esposito E |title=Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis |journal=Curr Drug Targets CNS Neurol Disord |volume=2 |issue=2 |pages=95–107 |year=2003 |pmid=12769802 |doi=10.2174/1568007033482959}}</ref><ref>{{cite journal |author=Rao A, Balachandran B |title=Role of oxidative stress and antioxidants in neurodegenerative diseases |journal=Nutr Neurosci |volume=5 |issue=5 |pages=291–309 |year=2002 |pmid=12385592 |doi=10.1080/1028415021000033767}}</ref> and as a way to prevent [[noise-induced hearing loss]].<ref>{{cite journal |author=Kopke RD, Jackson RL, Coleman JK, Liu J, Bielefeld EC, Balough BJ |title=NAC for noise: from the bench top to the clinic |journal=Hear. Res. |volume=226 |issue=1-2 |pages=114–25 |year=2007 |pmid=17184943 |doi=10.1016/j.heares.2006.10.008}}</ref> ===Disease prevention=== [[Image:Resveratrol.svg|thumb|right|270px|Structure of the [[polyphenol antioxidant]] [[resveratrol]].]] Antioxidants can cancel out the cell-damaging effects of free radicals.<ref name=Sies/> Furthermore, people who eat fruits and vegetables, which are good sources of antioxidants, have a lower risk of heart disease and some neurological diseases,<ref name=Stanner>{{cite journal |author=Stanner SA, Hughes J, Kelly CN, Buttriss J |title=A review of the epidemiological evidence for the 'antioxidant hypothesis' |journal=Public Health Nutr |volume=7 |issue=3 |pages=407–22 |year=2004 |pmid=15153272 |doi=10.1079/PHN2003543}}</ref> and there is evidence that some types of vegetables, and fruits in general, probably protect against a number of cancers.<ref>''[http://www.dietandcancerreport.org/?p=ER Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective]''. World Cancer Research Fund (2007). ISBN 978-0-9722522-2-5.</ref> These observations suggested that antioxidants might help prevent these conditions. There is some evidence that antioxidants might help prevent diseases such as [[macular degeneration]],<ref>{{cite journal |author=Bartlett H, Eperjesi F |title=Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials |journal=Ophthalmic Physiol Opt |volume=23 |issue=5 |pages=383–99 |year=2003 |pmid=12950886 |doi=10.1046/j.1475-1313.2003.00130.x}}</ref> suppressed [[immune system|immunity]] due to poor nutrition,<ref>{{cite journal |author=Wintergerst E, Maggini S, Hornig D |title=Immune-enhancing role of vitamin C and zinc and effect on clinical conditions |journal=Ann Nutr Metab |volume=50 |issue=2 |pages=85–94 |year=2006 |pmid=16373990 |doi=10.1159/000090495}}</ref> and neurodegeneration.<ref name="Wang">{{cite journal |author=Wang J, Wen L, Huang Y, Chen Y, Ku M |title=Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation |journal=Curr Pharm Des |volume=12 |issue=27 |pages=3521–33 |year=2006 |pmid=17017945 |doi=10.2174/138161206778343109}}</ref> However, despite the clear role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no reduction in either the risk of developing heart disease, or the rate of progression of existing disease.<ref>{{cite journal |author=Bleys J, Miller E, Pastor-Barriuso R, Appel L, Guallar E |title=Vitamin-mineral supplementation and the progression of atherosclerosis: a meta-analysis of randomized controlled trials |journal=Am. J. Clin. Nutr. |volume=84 |issue=4 |pages=880–7; quiz 954–5 |year=2006 |pmid=17023716}}</ref><ref>{{cite journal |author=Cook NR, Albert CM, Gaziano JM, ''et al'' |title=A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study |journal=Arch. Intern. Med. |volume=167 |issue=15 |pages=1610–8 |year=2007 |pmid=17698683 |doi=10.1001/archinte.167.15.1610}}</ref> This suggests that other substances in fruit and vegetables (possibly [[flavonoids]]), or a complex mix of substances, may contribute to the better cardiovascular health of those who consume more fruit and vegetables.<ref>{{cite journal |author=Cherubini A, Vigna G, Zuliani G, Ruggiero C, Senin U, Fellin R |title=Role of antioxidants in atherosclerosis: epidemiological and clinical update |journal=Curr Pharm Des |volume=11 |issue=16 |pages=2017–32 |year=2005 |pmid=15974956 |doi=10.2174/1381612054065783}}</ref><ref>{{cite journal |author=Lotito SB, Frei B |title=Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? |journal=Free Radic. Biol. Med. |volume=41 |issue=12 |pages=1727–46 |year=2006 |pmid=17157175 |doi=10.1016/j.freeradbiomed.2006.04.033}}</ref> It is thought that oxidation of low density lipoprotein in the blood contributes to heart disease, and initial observational studies found that people taking Vitamin E supplements had a lower risk of developing heart disease.<ref>{{cite journal | author=Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC | title=Vitamin E consumption and the risk of coronary heart disease in men | journal=N Engl J Med | year=1993 | pages=1450–6 | volume=328 | issue=20 | pmid=8479464 | doi=10.1056/NEJM199305203282004}}</ref> Consequently, at least seven large clinical trials were conducted to test the effects of antioxidant supplement with Vitamin E, in doses ranging from 50 to {{nowrap|600 mg}} per day. However, none of these trials found a statistically significant effect of Vitamin E on overall number of deaths or on deaths due to heart disease.<ref>{{cite journal | author=Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ | title=Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials | journal=Lancet | year=2003 | pages=2017–23 | volume=361 | issue=9374 | pmid=12814711 | doi=10.1016/S0140-6736(03)13637-9}}</ref> It is not clear if the doses used in these trials or in most dietary supplements are capable of producing any significant decrease in oxidative stress.<ref>{{cite journal |author=Roberts LJ, Oates JA, Linton MF, ''et al'' |title=The relationship between dose of vitamin E and suppression of oxidative stress in humans |journal=Free Radic. Biol. Med. |volume=43 |issue=10 |pages=1388–93 |year=2007 |pmid=17936185 |doi=10.1016/j.freeradbiomed.2007.06.019}}</ref> While several trials have investigated supplements with high doses of antioxidants, the "''Supplémentation en Vitamines et Mineraux Antioxydants''" (SU.VI.MAX) study tested the effect of supplementation with doses comparable to those in a healthy diet.<ref name=Hercberg>{{cite journal | author=Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, Roussel AM, Favier A, Briancon S | title=The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals | journal=Arch Intern Med | year=2004 | pages=2335–42 | volume=164 | issue=21 | pmid=15557412 | doi=10.1001/archinte.164.21.2335}}</ref> Over 12,500 French men and women took either low-dose antioxidants ({{nowrap|120 mg}} of ascorbic acid, {{nowrap|30 mg}} of vitamin E, {{nowrap|6 mg}} of beta carotene, 100 <math>\mu</math>g of selenium, and {{nowrap|20 mg}} of zinc) or [[placebo]] pills for an average of 7.5 years. The investigators found there was no statistically significant effect of the antioxidants on overall survival, cancer, or heart disease. However, a subgroup analysis showed a 31% reduction in the risk of cancer in men, but not women. Many [[nutraceutical]] and health food companies now sell formulations of antioxidants as dietary supplements and these are widely used in industrialized countries.<ref>{{cite journal |author=Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano M |title=Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999–2000 |url=http://aje.oxfordjournals.org/cgi/content/full/160/4/339 | doi = 10.1093/aje/kwh207 <!--Retrieved from url by DOI bot--> |journal=Am J Epidemiol |volume=160 |issue=4 |pages=339–49 |year=2004 |pmid=15286019}}</ref> These supplements may include specific antioxidant chemicals, like resveratrol (from grape seeds), combinations of antioxidants, like the "ACES" products that contain beta carotene (provitamin '''A'''), vitamin '''C''', vitamin '''E''' and '''S'''elenium, or herbs that contain antioxidants - such as [[green tea]] and [[jiaogulan]]. Although some levels of antioxidant vitamins and minerals in the diet are required for good health, there is considerable doubt as to whether antioxidant supplementation is beneficial, and if so, which antioxidant(s) are beneficial and in what amounts.<ref name=Shenkin>{{cite journal |author=Shenkin A |title=The key role of micronutrients |journal=Clin Nutr |volume=25 |issue=1 |pages=1–13 |year=2006 |pmid=16376462 |doi=10.1016/j.clnu.2005.11.006}}</ref><ref>{{cite journal |author=Woodside J, McCall D, McGartland C, Young I |title=Micronutrients: dietary intake v. supplement use |journal=Proc Nutr Soc |volume=64 |issue=4 |pages=543–53 |year=2005 |pmid=16313697 |doi=10.1079/PNS2005464}}</ref><ref name=Stanner/> It has been suggested that moderate levels of oxidative stress may increase life expectancy in the worm ''Caenorhabditis elegans'', by inducing a protective response to increased levels of reactive oxygen species.<ref>{{cite journal |author=Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M |title=Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress |journal=Cell Metab. |volume=6 |issue=4 |pages=280–93 |year=2007 |pmid=17908557 |doi=10.1016/j.cmet.2007.08.011}}</ref> However, the suggestion that increased life expectancy comes from increased oxidative stress conflicts with results seen in the yeast ''[[Saccharomyces cerevisiae]]'',<ref>{{cite journal |author=Barros MH, Bandy B, Tahara EB, Kowaltowski AJ |title=Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae |journal=J. Biol. Chem. |volume=279 |issue=48 |pages=49883–8 |year=2004 |pmid=15383542 |doi=10.1074/jbc.M408918200}}</ref> and the situation in mammals is even less clear.<ref name = "hdanrt"/><ref>{{cite journal |author=Sohal R |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=10.1016/S0891-5849(02)00856-0}}</ref><ref>{{cite journal |author=Rattan S |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> ===Physical exercise=== During exercise, oxygen consumption can increase by a factor of more than 10.<ref>{{cite journal |author=Dekkers J, van Doornen L, Kemper H |title=The role of antioxidant vitamins and enzymes in the prevention of exercise-induced muscle damage |journal=Sports Med |volume=21 |issue=3 |pages=213–38 |year=1996 |pmid=8776010 |doi=10.2165/00007256-199621030-00005}}</ref> This leads to a large increase in the production of oxidants and results in damage that contributes to muscular fatigue during and after exercise. The [[inflammatory response]] that occurs after strenuous exercise is also associated with oxidative stress, especially in the 24 hours after an exercise session. The immune system response to damage done by exercise peaks 2 to 7 days after exercise, the period during which adaptation resulting in greater fitness is greatest. During this process, free radicals are produced by [[neutrophil]]s to remove damaged tissue. As a result, excessive antioxidant levels have the potential to inhibit recovery and adaptation mechanisms.<ref>{{cite journal |author=Tiidus P |title=Radical species in inflammation and overtraining |url=http://article.pubs.nrc-cnrc.gc.ca/ppv/RPViewDoc?issn=0008-4212&volume=76&issue=5&startPage=533 |journal=Can J Physiol Pharmacol |volume=76 |issue=5 |pages=533–8 |year=1998 |pmid=9839079 |doi=10.1139/cjpp-76-5-533}}</ref> The evidence for benefits from antioxidant supplementation in vigorous exercise is mixed. There is strong evidence that one of the adaptations resulting from exercise is a strengthening of the body's antioxidant defenses, particularly the glutathione system, to deal with the increased oxidative stress.<ref>{{cite journal |author=Leeuwenburgh C, Fiebig R, Chandwaney R, Ji L |title=Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems |url=http://ajpregu.physiology.org/cgi/reprint/267/2/R439 |journal=Am J Physiol |volume=267 |issue=2 Pt 2 |pages=R439–45 |year=1994 |pmid=8067452}}</ref> It is possible that this effect may be to some extent protective against diseases which are associated with oxidative stress, which would provide a partial explanation for the lower incidence of major diseases and better health of those who undertake regular exercise.<ref>{{cite journal |author=Leeuwenburgh C, Heinecke J |title=Oxidative stress and antioxidants in exercise |journal=Curr Med Chem |volume=8 |issue=7 |pages=829–38 |year=2001 |pmid=11375753}}</ref> However, no benefits for physical performance to athletes are seen with vitamin E supplementation.<ref>{{cite journal |author=Takanami Y, Iwane H, Kawai Y, Shimomitsu T |title=Vitamin E supplementation and endurance exercise: are there benefits? |journal=Sports Med |volume=29 |issue=2 |pages=73–83 |year=2000 |pmid=10701711 |doi=10.2165/00007256-200029020-00001}}</ref> Indeed, despite its key role in preventing lipid membrane peroxidation, 6 weeks of vitamin E supplementation had no effect on muscle damage in ultramarathon runners.<ref>{{cite journal |author=Mastaloudis A, Traber M, Carstensen K, Widrick J |title=Antioxidants did not prevent muscle damage in response to an ultramarathon run |journal=Med Sci Sports Exerc |volume=38 |issue=1 |pages=72–80 |year=2006 |pmid=16394956 |doi=10.1249/01.mss.0000188579.36272.f6}}</ref> Although there appears to be no increased requirement for vitamin C in athletes, there is some evidence that vitamin C supplementation increased the amount of intense exercise that can be done and vitamin C supplementation before strenuous exercise may reduce the amount of muscle damage.<ref>{{cite journal |author=Peake J |title=Vitamin C: effects of exercise and requirements with training |journal=Int J Sport Nutr Exerc Metab |volume=13 |issue=2 |pages=125–51 |year=2003 |pmid=12945825}}</ref><ref>{{cite journal |author=Jakeman P, Maxwell S |title=Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise |journal=Eur J Appl Physiol Occup Physiol |volume=67 |issue=5 |pages=426–30 |year=1993 |pmid=8299614 |doi=10.1007/BF00376459}}</ref> However, other studies found no such effects, and some research suggests that supplementation with amounts as high as {{nowrap|1000 mg}} inhibits recovery.<ref>{{cite journal |author=Close G, Ashton T, Cable T, Doran D, Holloway C, McArdle F, MacLaren D |title=Ascorbic acid supplementation does not attenuate post-exercise muscle soreness following muscle-damaging exercise but may delay the recovery process |journal=Br J Nutr |volume=95 |issue=5 |pages=976–81 |year=2006 |pmid=16611389 |doi=10.1079/BJN20061732}}</ref> ===Adverse effects=== {{further|[[Micronutrient]]s}} [[Image:Phytate.png|thumb|230px|right|Structure of the metal chelator [[phytic acid]].]] Relatively strong reducing acids can have anti-nutritional effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed.<ref>{{cite journal |author=Hurrell R |title=Influence of vegetable protein sources on trace element and mineral bioavailability |url=http://jn.nutrition.org/cgi/content/full/133/9/2973S |journal=J Nutr |volume=133 |issue=9 |pages=2973S–7S |year=2003 |pmid=12949395}}</ref> Notable examples are [[oxalic acid]], [[tannin]]s and [[phytic acid]], which are high in plant-based diets.<ref>{{cite journal |author=Hunt J |title=Bioavailability of iron, zinc, and other trace minerals from vegetarian diets |url=http://www.ajcn.org/cgi/content/full/78/3/633S |journal=Am J Clin Nutr |volume=78 |issue=3 Suppl |pages=633S–639S |year=2003 |pmid=12936958}}</ref> [[Calcium]] and iron deficiencies are not uncommon in diets in [[developing country|developing countries]] where less meat is eaten and there is high consumption of phytic acid from beans and unleavened [[whole grain]] bread.<ref>{{cite journal |author=Gibson R, Perlas L, Hotz C |title=Improving the bioavailability of nutrients in plant foods at the household level |journal=Proc Nutr Soc |volume=65 |issue=2 |pages=160–8 |year=2006 |pmid=16672077 |doi=10.1079/PNS2006489}}</ref> {| class="wikitable" style="margin-left: auto; margin-right: auto;" !Foods !Reducing acid present |- |align="center" |[[Cocoa]] and [[chocolate]], [[spinach]], [[turnip]] and [[rhubarb]].<ref name=Mosha>{{cite journal |author=Mosha T, Gaga H, Pace R, Laswai H, Mtebe K |title=Effect of blanching on the content of antinutritional factors in selected vegetables |journal=Plant Foods Hum Nutr |volume=47 |issue=4 |pages=361–7 |year=1995 |pmid=8577655 |doi=10.1007/BF01088275}}</ref> |align="center" |[[Oxalic acid]] |- |align="center" |[[Whole grains]], [[maize]], [[legume]]s.<ref>{{cite journal |author=Sandberg A |title=Bioavailability of minerals in legumes |journal=Br J Nutr |volume=88 Suppl 3 |issue= |pages=S281–5 |year=2002 |pmid=12498628 |doi=10.1079/BJN/2002718}}</ref> |align="center" |[[Phytic acid]] |- |align="center" |[[Tea]], [[beans]], [[cabbage]].<ref name=Beecher>{{cite journal |author=Beecher G |title=Overview of dietary flavonoids: nomenclature, occurrence and intake |url=http://jn.nutrition.org/cgi/content/full/133/10/3248S |journal=J Nutr |volume=133 |issue=10 |pages=3248S–3254S |year=2003 |pmid=14519822}}</ref><ref name=Mosha/> |align="center" |[[Tannins]] |} [[Nonpolar]] antioxidants such as [[eugenol]], a major component of [[oil of cloves]] have toxicity limits that can be exceeded with the misuse of undiluted [[essential oil]]s.<ref>{{cite journal |author=Prashar A, Locke I, Evans C |title=Cytotoxicity of clove (Syzygium aromaticum) oil and its major components to human skin cells |journal=Cell Prolif |volume=39 |issue=4 |pages=241–8 |year=2006 |pmid=16872360 |doi=10.1111/j.1365-2184.2006.00384.x}}</ref> Toxicity associated with high doses of water-soluble antioxidants such as ascorbic acid are less of a concern, as these compounds can be excreted rapidly in [[urine]].<ref>{{cite journal |author=Hornig D, Vuilleumier J, Hartmann D |title=Absorption of large, single, oral intakes of ascorbic acid |journal=Int J Vitam Nutr Res |volume=50 |issue=3 |pages=309–14 |year=1980 |pmid=7429760}}</ref> More seriously, very high doses of some antioxidants may have harmful long-term effects. The beta-Carotene and Retinol Efficacy Trial (CARET) study of lung cancer patients found that smokers given supplements containing beta-carotene and vitamin A had increased rates of lung cancer.<ref>{{cite journal |author=Omenn G, Goodman G, Thornquist M, Balmes J, Cullen M, Glass A, Keogh J, Meyskens F, Valanis B, Williams J, Barnhart S, Cherniack M, Brodkin C, Hammar S |title=Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial |journal=J Natl Cancer Inst |volume=88 |issue=21 |pages=1550–9 |year=1996 |pmid=8901853 |doi=10.1093/jnci/88.21.1550}}</ref> Subsequent studies confirmed these adverse effects.<ref>{{cite journal |author=Albanes D |title=Beta-carotene and lung cancer: a case study |url=http://www.ajcn.org/cgi/content/full/69/6/1345S |journal=Am J Clin Nutr |volume=69 |issue=6 |pages=1345S–1350S |year=1999 |pmid=10359235}}</ref> These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 230,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality but saw no significant effect from vitamin C.<ref name=Bjelakovic>{{cite journal |author=Bjelakovic G, Nikolova D, Gluud L, Simonetti R, Gluud C |title=Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis |url=http://jama.ama-assn.org/cgi/content/abstract/297/8/842 |journal=JAMA |volume=297 |issue=8 |pages=842–57 |year=2007 |pmid=17327526 |doi=10.1001/jama.297.8.842}}</ref> No health risk was seen when all the randomized controlled studies were examined together, but an increase in mortality was detected only when the high-quality and low-bias risk trials were examined separately. However, as the majority of these low-bias trials dealt with either elderly people, or people already suffering disease, these results may not apply to the general population.<ref>[http://www.sciencedaily.com/releases/2007/02/070228172604.htm Study Citing Antioxidant Vitamin Risks Based On Flawed Methodology, Experts Argue] News release from Oregon State University published on ScienceDaily, Accessed 19 April 2007</ref> This meta-analysis was later repeated and extended by the same authors, with the new analysis published by the [[Cochrane Collaboration]]; confirming the previous results.<ref>{{cite journal |author=Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C |title=Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases |journal=Cochrane Database of Systematic Reviews |issue=2 |pages=CD007176 |year=2008 |doi=10.1002/14651858.CD007176}}</ref> These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality,<ref>{{cite journal |author=Miller E, Pastor-Barriuso R, Dalal D, Riemersma R, Appel L, Guallar E |title=Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality |journal=Ann Intern Med |volume=142 |issue=1 |pages=37–46 |year=2005 |pmid=15537682}}</ref> and that antioxidant supplements increased the risk of colon cancer.<ref>{{cite journal |author=Bjelakovic G, Nagorni A, Nikolova D, Simonetti R, Bjelakovic M, Gluud C |title=Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma |journal=Aliment Pharmacol Ther |volume=24 |issue=2 |pages=281–91 |year=2006 |pmid=16842454 |doi=10.1111/j.1365-2036.2006.02970.x}}</ref> However, the results of this meta-analysis are inconsistent with other studies such as the SU.VI.MAX trial, which suggested that antioxidants have no effect on cause-all mortality.<ref name=Hercberg/><ref>{{cite journal |author=Caraballoso M, Sacristan M, Serra C, Bonfill X |title=Drugs for preventing lung cancer in healthy people |journal=Cochrane Database Syst Rev |volume= |issue= |pages=CD002141 |year=2003 |pmid=12804424}}</ref><ref>{{cite journal |author=Bjelakovic G, Nagorni A, Nikolova D, Simonetti R, Bjelakovic M, Gluud C |title=Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma |journal=Aliment. Pharmacol. Ther. |volume=24 |issue=2 |pages=281–91 |year=2006 |pmid=16842454 |doi=10.1111/j.1365-2036.2006.02970.x}}</ref><ref>{{cite journal |author=Coulter I, Hardy M, Morton S, Hilton L, Tu W, Valentine D, Shekelle P |title=Antioxidants vitamin C and vitamin e for the prevention and treatment of cancer |journal=Journal of general internal medicine: official journal of the Society for Research and Education in Primary Care Internal Medicine |volume=21 |issue=7 |pages=735–44 |year=2006 |pmid=16808775}}</ref> Overall, the large number of clinical trials carried out on antioxidant supplements suggest that either these products have no effect on health, or that they cause a small increase in mortality in elderly or vulnerable populations.<ref name=Shenkin/><ref name=Stanner/><ref name=Bjelakovic/> While antioxidant supplementation is widely used in attempts to prevent the development of cancer, it has been proposed that antioxidants may, paradoxically, interfere with cancer treatments.<ref>{{cite journal | author = Schumacker P | title = Reactive oxygen species in cancer cells: Live by the sword, die by the sword. | journal = Cancer Cell | volume = 10 | issue = 3 | pages = 175–6 | year = 2006 | pmid = 16959608 | doi = 10.1016/j.ccr.2006.08.015}}</ref> This was thought to occur since the environment of cancer cells causes high levels of oxidative stress, making these cells more susceptible to the further oxidative stress induced by treatments. As a result, by reducing the redox stress in cancer cells, antioxidant supplements were thought to decrease the effectiveness of [[radiotherapy]] and [[chemotherapy]].<ref>{{cite journal |author=Seifried H, McDonald S, Anderson D, Greenwald P, Milner J |title=The antioxidant conundrum in cancer |url=http://cancerres.aacrjournals.org/cgi/content/full/63/15/4295 |journal=Cancer Res |volume=63 |issue=15 |pages=4295–8 |year=2003 |pmid=12907593}}</ref> However, this concern appears not to be valid, as it has been addressed by multiple clinical trials that indicate that antioxidants are either neutral or beneficial in cancer therapy.<ref>{{cite journal |author=Simone C, Simone N, Simone V, Simone C |title=Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1 |journal=Alternative therapies in health and medicine |volume=13 |issue=1 |pages=22–8 |year=2007 |pmid=17283738}}</ref><ref>{{cite journal |author=Moss R |title=Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? |journal=Integrative cancer therapies |volume=5 |issue=1 |pages=63–82 |year=2006 |pmid=16484715 |doi=10.1177/1534735405285882}}</ref> ==Measurement and levels in food== {{further|[[List of antioxidants in food]], [[Polyphenol antioxidant]]s}} [[Image:Vegetarian diet.jpg|right|thumb|[[Fruit]]s and [[vegetable]]s are good sources of antioxidants.]] Measurement of antioxidants is not a straightforward process, as this is a diverse group of compounds with different reactivities to different reactive oxygen species. In [[food science]], the [[oxygen radical absorbance capacity]] (ORAC) has become the current industry standard for assessing antioxidant strength of whole foods, juices and food additives.<ref>{{cite journal |author=Cao G, Alessio H, Cutler R |title=Oxygen-radical absorbance capacity assay for antioxidants |journal=Free Radic Biol Med |volume=14 |issue=3 |pages=303–11 |year=1993 |pmid=8458588 |doi=10.1016/0891-5849(93)90027-R}}</ref><ref>{{cite journal |author=Ou B, Hampsch-Woodill M, Prior R |title=Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe |journal=J Agric Food Chem |volume=49 |issue=10 |pages=4619–26 |year=2001 |pmid=11599998 |doi=10.1021/jf010586o}}</ref> Other measurement tests include the [[Folin-Ciocalteu reagent]], and the [[Oxygen Radical Absorbance Capacity|trolox equivalent antioxidant capacity assay]].<ref>{{cite journal |author=Prior R, Wu X, Schaich K |title=Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements |journal=J Agric Food Chem |volume=53 |issue=10 |pages=4290–302 |year=2005 |pmid=15884874 |doi=10.1021/jf0502698}}</ref> In medicine, a range of different assays are used to assess the antioxidant capability of blood plasma and of these, the ORAC assay may be the most reliable.<ref>{{cite journal |author=Cao G, Prior R |title=Comparison of different analytical methods for assessing total antioxidant capacity of human serum |url=http://www.clinchem.org/cgi/content/full/44/6/1309 |journal=Clin Chem |volume=44 |issue=6 Pt 1 |pages=1309–15 |year=1998 |pmid=9625058}}</ref> Antioxidants are found in varying amounts in foods such as vegetables, fruits, grain cereals, legumes and nuts. Some antioxidants such as [[lycopene]] and ascorbic acid can be destroyed by long-term storage or prolonged cooking.<ref>{{cite journal |author=Xianquan S, Shi J, Kakuda Y, Yueming J |title=Stability of lycopene during food processing and storage |journal=J Med Food |volume=8 |issue=4 |pages=413–22 |year=2005 |pmid=16379550 |doi=10.1089/jmf.2005.8.413}}</ref><ref>{{cite journal |author=Rodriguez-Amaya D |title=Food carotenoids: analysis, composition and alterations during storage and processing of foods |journal=Forum Nutr |volume=56 |issue= |pages=35–7 |year=2003 |pmid=15806788}}</ref> Other antioxidant compounds are more stable, such as the polyphenolic antioxidants in foods such as whole-wheat cereals and tea.<ref>{{cite journal |author=Baublis A, Lu C, Clydesdale F, Decker E |title=Potential of wheat-based breakfast cereals as a source of dietary antioxidants |url=http://www.jacn.org/cgi/content/full/19/suppl_3/308S |journal=J Am Coll Nutr |volume=19 |issue=3 Suppl |pages=308S–311S |year=2000 |pmid=10875602}}</ref><ref>{{cite journal |author=Rietveld A, Wiseman S |title=Antioxidant effects of tea: evidence from human clinical trials |url=http://jn.nutrition.org/cgi/content/full/133/10/3285S |journal=J Nutr |volume=133 |issue=10 |pages=3285S–3292S |year=2003 |pmid=14519827}}</ref> In general, processed foods contain less antioxidants than fresh and uncooked foods, since the preparation processes may expose the food to oxygen.<ref>{{cite journal |author=Henry C, Heppell N |title=Nutritional losses and gains during processing: future problems and issues |url=http://docstore.ingenta.com/cgi-bin/ds_deliver/1/u/d/ISIS/35722612.1/cabi/pns/2002/00000061/00000001/art00020/4A4C97E12AA663421172630098BC02E4E69AEC9E94.pdf?link=http://www.ingentaconnect.com/error/delivery&format=pdf |journal=Proc Nutr Soc |volume=61 |issue=1 |pages=145–8 |year=2002 |pmid=12002789}}</ref> {| class="wikitable" style="margin-left: auto; margin-right: auto;" !Antioxidant compounds !Foods containing high levels of these antioxidants<ref>{{cite web | title=Antioxidants and Cancer Prevention: Fact Sheet |publisher=National Cancer Institute | url=http://www.cancer.gov/cancertopics/factsheet/antioxidantsprevention|accessdate=2007-02-27}}</ref><ref name=Beecher/><ref>{{cite journal |author=Ortega RM |title=Importance of functional foods in the Mediterranean diet |journal=Public Health Nutr |volume=9 |issue=8A |pages=1136–40 |year=2006 |pmid=17378953 |doi=10.1017/S1368980007668530}}</ref> |- |Vitamin C (ascorbic acid) |[[Fruits]] and [[vegetables]] |- |Vitamin E (tocopherols, tocotrienols) |[[Vegetable oil]]s |- |Polyphenolic antioxidants (resveratrol, [[flavonoid]]s) |Tea, [[coffee]], [[soy]], [[fruit]], [[olive oil]], chocolate, [[oregano]] and [[wine|red wine]]. |- |[[Carotenoid]]s (lycopene, carotenes) |Fruit and vegetables |- |} Some antioxidants are made in the body and are not absorbed from the [[intestine]]. One example is glutathione, which is made from amino acids. As any glutathione in the gut is broken down to free cysteine, [[glycine]] and [[glutamic acid]] before being absorbed, even large oral doses have little effect on the concentration of glutathione in the body.<ref>{{cite journal |author=Witschi A, Reddy S, Stofer B, Lauterburg B |title=The systemic availability of oral glutathione |journal=Eur J Clin Pharmacol |volume=43 |issue=6 |pages=667–9 |year=1992 |pmid=1362956 |doi=10.1007/BF02284971}}</ref> [[Ubiquinol]] (coenzyme Q) is also poorly absorbed from the gut and is made in humans through the [[mevalonate pathway]].<ref name=Turunen/> ==Uses in technology== ===Food preservatives=== Antioxidants are used as [[food additive]]s to help [[preservative|guard against food deterioration]]. Exposure to oxygen and sunlight are the two main factors in the oxidation of food, so food is preserved by keeping in the dark and sealing it in containers or even coating it in wax, as with cucumbers. However, as oxygen is also important for plant [[Respiration (physiology)|respiration]], storing plant materials in [[anaerobic]] conditions produces unpleasant flavors and unappealing colors.<ref>{{cite journal |author=Kader A, Zagory D, Kerbel E |title=Modified atmosphere packaging of fruits and vegetables |journal=Crit Rev Food Sci Nutr |volume=28 |issue=1 |pages=1–30 |year=1989 |pmid=2647417}}</ref> Consequently, packaging of fresh fruits and vegetables contains an ~8% oxygen atmosphere. Antioxidants are an especially important class of preservatives as, unlike [[bacteria]]l or [[fungus|fungal]] spoilage, oxidation reactions still occur relatively rapidly in frozen or refrigerated food.<ref>{{cite journal |author=Zallen E, Hitchcock M, Goertz G |title=Chilled food systems. Effects of chilled holding on quality of beef loaves |journal=J Am Diet Assoc |volume=67 |issue=6 |pages=552–7 |year=1975 |pmid=1184900}}</ref> These preservatives include ascorbic acid (AA, E300), [[propyl gallate]] (PG, E310), tocopherols (E306), [[tert-Butylhydroquinone|tertiary butylhydroquinone]] (TBHQ), [[butylated hydroxyanisole]] (BHA, E320) and [[butylated hydroxytoluene]] (BHT, E321).<ref>{{cite journal |author=Iverson F |title=Phenolic antioxidants: Health Protection Branch studies on butylated hydroxyanisole |journal=Cancer Lett |volume=93 |issue=1 |pages=49–54 |year=1995 |pmid=7600543 |doi=10.1016/0304-3835(95)03787-W}}</ref><ref>{{cite web | title=E number index |publisher=UK food guide | url=http://www.ukfoodguide.net/enumeric.htm#antioxidants |accessdate=2007-03-05}}</ref> The most common molecules attacked by oxidation are unsaturated fats; oxidation causes them to turn [[rancidification|rancid]].<ref>{{cite journal |author=Robards K, Kerr A, Patsalides E |title=Rancidity and its measurement in edible oils and snack foods. A review |journal=Analyst |volume=113 |issue=2 |pages=213–24 |year=1988 |pmid=3288002 |doi=10.1039/an9881300213}}</ref> Since oxidized lipids are often discolored and usually have unpleasant tastes such as metallic or [[sulfur]]ous flavors, it is important to avoid oxidation in fat-rich foods. Thus, these foods are rarely preserved by drying; instead, they are preserved by [[Smoking (cooking technique)|smoking]], [[salting (food)|salting]] or [[fermentation (food)|fermenting]]. Even less fatty foods such as fruits are sprayed with sulfurous antioxidants prior to air drying. Oxidation is often catalyzed by metals, which is why fats such as butter should never be wrapped in [[aluminium foil]] or kept in metal containers. Some fatty foods such as olive oil are partially protected from oxidation by their natural content of antioxidants, but remain sensitive to photooxidation.<ref>{{cite journal |author=Del Carlo M, Sacchetti G, Di Mattia C, Compagnone D, Mastrocola D, Liberatore L, Cichelli A |title=Contribution of the phenolic fraction to the antioxidant activity and oxidative stability of olive oil |journal=J Agric Food Chem |volume=52 |issue=13 |pages=4072–9 |year=2004 |pmid=15212450 |doi=10.1021/jf049806z}}</ref> ===Industrial uses=== Some antioxidants are added to industrial products. A common use is as [[Gasoline additive|stabilizers]] in [[fuel]]s and [[lubricant]]s to prevent oxidation, and in gasolines to prevent the polymerization that leads to the formation of engine-fouling residues.<ref>CE Boozer, GS Hammond, CE Hamilton (1955) "Air Oxidation of Hydrocarbons. The Stoichiometry and Fate of Inhibitors in Benzene and Chlorobenzene". ''Journal of the American Chemical Society'', 3233–3235</ref> They are also used to prevent the oxidative degradation of rubber, [[plastic]]s and [[adhesive]]s that causes a loss of strength and flexibility in these materials.<ref>{{cite web | title=Why use Antioxidants? |publisher=SpecialChem Adhesives | url=http://www.specialchem4adhesives.com/tc/antioxidants/index.aspx?id= |accessdate=2007-02-27}}</ref> Antioxidant preservatives are also added to fat-based [[cosmetics]] such as [[lipstick]] and [[moisturizer]]s to prevent rancidity. {| class="wikitable" style="margin-left: auto; margin-right: auto;" !Fuel additive !Components<ref name=innospec>{{cite web | title=Fuel antioxidants |publisher=Innospec Chemicals | url=http://www.innospecinc.com/americas/products/fuel_antitoxidants.cfm |accessdate=2007-02-27}}</ref> !Applications<ref name=innospec/> |- |align="center" |AO-22 |align="center" |[[N,N'-di-2-butyl-1,4-phenylenediamine]] |align="center" |Turbine oils, [[transformer oil]]s, [[hydraulic fluid]]s, [[wax]]es, and [[grease (lubricant)|greases]] |- |align="center" |AO-24 |align="center" |N,N'-di-2-butyl-1,4-phenylenediamine |align="center" |Low-temperature oils |- |align="center" |AO-29 |align="center" |[[2,6-di-tert-butyl-4-methylphenol]] |align="center" |Turbine oils, transformer oils, hydraulic fluids, waxes, greases, and gasolines |- |align="center" |AO-30 |align="center" |[[2,4-dimethyl-6-tert-butylphenol]] |align="center" |[[Jet fuel]]s and gasolines, including aviation gasolines |- |align="center" |AO-31 |align="center" |2,4-dimethyl-6-tert-butylphenol |align="center" |Jet fuels and gasolines, including aviation gasolines |- |align="center" |AO-32 |align="center" |2,4-dimethyl-6-tert-butylphenol and 2,6-di-tert-butyl-4-methylphenol |align="center" |Jet fuels and gasolines, including aviation gasolines |- |align="center" |AO-37 |align="center" |[[2,6-di-tert-butylphenol]] |align="center" |Jet fuels and gasolines, widely approved for [[aviation fuel]]s |- |} ==See also== * [[Evolution of dietary antioxidants]] * [[Free radical theory]] * [[Life extension]] * [[Nootropics]] * [[Nutrition]] * [[Phytochemical]] * [[hormesis|Mitohormesis]] * [[List of phytochemicals and foods in which they are prominent]] * [[Polymer degradation]] * [[Forensic polymer engineering]] ==Further reading== * Nick Lane ''Oxygen: The Molecule That Made the World'' (Oxford University Press, 2003) ISBN 0-198-60783-0 * Barry Halliwell and John M.C. Gutteridge ''Free Radicals in Biology and Medicine''(Oxford University Press, 2007) ISBN 0-198-56869-X * Jan Pokorny, Nelly Yanishlieva and Michael H. Gordon ''Antioxidants in Food: Practical Applications'' (CRC Press Inc, 2001) ISBN 0-849-31222-1 <!---See [[Wikipedia:Guide_to_layout#Standard_appendices_and_descriptions]], external links and further reading do NOT have to go last --> ==External links== <!--===========================({{NoMoreLinks}})=============================== | DO NOT ADD MORE LINKS TO THIS ARTICLE. WIKIPEDIA IS NOT A COLLECTION OF | | LINKS. If you think that your link might be useful, do not add it here, | | but put it on this article's discussion page first or submit your link | | to the appropriate category at the Open Directory Project (www.dmoz.org)| | and link back to that category using the {{dmoz}} template. | | | | Links that have not been verified WILL BE DELETED. | | See [[Wikipedia:External links]] and [[Wikipedia:Spam]] for details | ===========================({{NoMoreLinks}})===============================--> * [http://www.ext.colostate.edu/pubs/columnnn/nn000322.html Foods that are rich in antioxidants] * [http://ods.od.nih.gov/index.aspx U.S. National Institute Health, Office on Dietary Supplements] * [http://www.ific.org/publications/factsheets/antioxidantfs.cfm List of antioxidants, food sources, and Potential Benefits] * [http://www.nlm.nih.gov/medlineplus/antioxidants.html MedlinePlus: Antioxidants.] ==References== {{reflist|2}} {{featured article}} [[Category:Antioxidants]] [[Category:Physiology]] {{Link FA|es}} [[ar:مضاد التأكسد]] [[ca:Antioxidant]] [[cs:Antioxidant]] [[da:Antioxidant]] [[de:Antioxidantien]] [[es:Antioxidante]] [[eo:Antioksidanto]] [[fa:آنتی اکسیدانت]] [[fr:Antioxydant]] [[gl:Antioxidante]] [[id:Antioksidan]] [[it:Antiossidante]] [[he:נוגד חמצון]] [[hu:Antioxidáns]] [[ms:Bahan antioksida]] [[nl:Antioxidant]] [[ja:酸化防止剤]] [[no:Antioksidant]] [[nn:Antioksidant]] [[pl:Przeciwutleniacze]] [[pt:Antioxidante]] [[ru:Антиоксиданты]] [[sk:Antioxidant]] [[su:Antioksidan]] [[fi:Antioksidantti]] [[sv:Antioxidant]] [[th:สารต้านอนุมูลอิสระ]] [[tr:Antioksidan]] [[uk:Антиоксиданти]] [[zh:抗氧化剂]]