Antioxidant

AntioxidantFrom Wikipedia, the free encyclopedia Model of the antioxidant metabolite glutathione. The yellow sphere is the 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 that inhibits the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When the chain reaction occurs in a cell, it can cause damage or death to the cell. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions. They do this by being oxidized themselves, so antioxidants are often reducing agents such asthiols, ascorbic acid, or polyphenols.[1] Antioxidants are important additives in gasoline. These antioxidants prevent the formation of gums that interfere with the operation of internal combustion engines.[2] Substituted phenols and derivatives ofphenylenediamine are common antioxidants used to inhibit gum formation in gasoline (petrol). Although oxidation reactions are crucial for life, they can also be damaging; plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Insufficient levels of antioxidants, or inhibition of the antioxidant enzymes, cause oxidative stress and may damage or kill cells. As oxidative stress appears to be an important part of many human diseases, the use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. Moreover, oxidative stress is both the cause and the consequence of disease. Antioxidants are widely used in dietary supplements and have been investigated for the prevention of diseases such as cancer, coronary heart disease and even altitude sickness. Although initial studies suggested that antioxidant supplements might promote health, later large clinical trialswith a limited number of antioxidants detected no benefit and even suggested that excess supplementation with certain putative antioxidants may be harmful.[3][4][5] Antioxidants also have many industrial uses, such as preservatives in food and cosmetics and to prevent the degradation of rubber and gasoline. Contents [hide] • • • o o o o o o • o • o o 1 History 2 The oxidative challenge in biology 3 Metabolites 3.1 Overview 3.2 Uric acid 3.3 Ascorbic acid 3.4 Glutathione 3.5 Melatonin 3.6 Tocopherols and tocotrienols (vitamin E) 4 Pro-oxidant activities 4.1 Potential of antioxidant supplements to damage health 5 Enzyme systems 5.1 Overview 5.2 Superoxide dismutase, catalase and peroxiredoxins o • • o o o 5.3 Thioredoxin and glutathione systems 6 Oxidative stress in disease 7 Potential health effects 7.1 Organ function 7.2 Relation to diet 7.3 Physical exercise o o • o o • • • • 7.4 Adverse effects 7.5 Measurement and levels in food 8 Uses in technology 8.1 Food preservatives 8.2 Industrial uses 9 See also 10 References 11 Further reading 12 External links [edit]History As part of their adaptation from marine life, terrestrial plants began producing non-marine antioxidants such as ascorbic acid (Vitamin C), polyphenols and tocopherols. The evolution of angiospermplants between 50 and 200 million years ago resulted in the development of many antioxidant pigments – particularly during the Jurassic period – as chemical defences against reactive oxygen species that are byproducts of photosynthesis.[6] Originally, the term antioxidant specifically referred to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th centuries, extensive study concentrated on the use of antioxidants in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerizationof fuels in the fouling of internal combustion engines.[7] Early research on the role of antioxidants in biology focused on their use in preventing the oxidation of unsaturated fats, which is the cause of rancidity.[8] 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 vitamins A, C, and E as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in the biochemistry of living organisms.[9][10] 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.[11] 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 scavenging reactive oxygen species before they can damage cells.[12] [edit]The oxidative challenge in biology Further information: Oxidative stress The structure of the antioxidant vitaminascorbic acid (vitamin C). A paradox in metabolism is that, while the vast majority of complex life on Earth requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species.[13] Consequently, organisms contain a complex network of antioxidantmetabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids.[1][14] In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell.[1][13]However, reactive oxygen species also have useful cellular functions, such as redox signaling. Thus, the function of antioxidant systems is not to remove oxidants entirely, but instead to keep them at an optimum level.[15] The reactive oxygen species produced in cells include hydrogen peroxide (H2O2), hypochlorous acid (HClO), and free radicals such as the hydroxyl radical (·OH) and the superoxide anion (O2−).[16] 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 metal-catalyzed redox reactions such as the Fenton reaction.[17] These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins.[1] Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms,[18][19] while damage to proteins causes enzyme inhibition,denaturation and protein degradation.[20] The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species. [21] In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.[22] Particularly important is the reduction of coenzyme Q in complex III, since a highly reactive free radical is formed as an intermediate (Q·−). 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 wellcontrolled reactions of the electron transport chain.[23] Peroxide is also produced from the oxidation of reduced flavoproteins, such as complex I.[24] However, although these enzymes can produce oxidants, the relative importance of the electron transfer chain to other processes that generate peroxide is unclear.[25][26] In algae.400 (human)[37] .[14] The different antioxidants are present at a wide range of concentrations in body fluids and tissues. reactive oxygen species are also produced during photosynthesis. which is the function of iron-binding proteins such as transferrin and ferritin.[26] Selenium and zinc are commonly referred to as antioxidant nutrients.[33] [34] The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system. while lipid-soluble antioxidants protect cell membranes from lipid peroxidation.[1] These compounds may be synthesized in the body or obtained from the diet. [27] particularly under conditions of high light intensity.[14] Some compounds contribute to antioxidant defense by chelating transition metals and preventing them from catalyzing the production of free radicals in the cell.[14] The amount of protection provided by any one antioxidant will also depend on its concentration. Antioxidant metabolite Solubility Concentration in human serum (μM)[35] Concentration in liver tissue (μmol/kg) Ascorbic acid (vitamin C) Water 50 – 60[36] 260 (human)[37] Glutathione Water 4[38] 6.[32] The relative importance and interactions between these different antioxidants is a very complex question. Particularly important is the ability to sequester iron. by large amount of iodide and selenium. with some such as glutathione or ubiquinone mostly present within cells.[30][31] [edit]Metabolites [edit]Overview Antioxidants are classified into two broad divisions. depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic).plants. In general. its reactivity towards the particular reactive oxygen species being considered.[28] This effect is partly offset by the involvement ofcarotenoids in photoinhibition. with the various metabolites and enzyme systems having synergistic and interdependent effects on one another. while others such as uric acid are more evenly distributed (see table below). and cyanobacteria. Some antioxidants are only found in a few organisms and these compounds can be important in pathogens and can be virulence factors. and in algae and cyanobacteria. and the status of the antioxidants with which it interacts. [29] which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species. water-soluble antioxidants react with oxidants in the cell cytosol and the blood plasma. but these chemical elements have no antioxidant action themselves and are instead required for the activity of some antioxidant enzymes. as is discussed below. the administration of UA is therapeutic in experimental allergic encephalomyelitis (EAE).600 (human)[37] Carotenes Lipid β-carotene: 0.[48][49] The evolutionary reasons for this loss of urate converstion to allantoin remain the topic of active speculation. Gwen Scott explains the significance of uric acid as an antioxidant by proposing that "Serum UA levels are inversely associated with the incidence of MS in humans because MS patients have low serum UA levels and individuals with hyperuricemia (gout) rarely develop the disease. leading researchers to propose this is due to UA's antioxidant properties. an animal model of MS. the claim that its levels affect MS risk is still controversial."[55][57][58] In sum. Moreover.[61] Uric acid's antioxidant activities are also complex. introduction of UA both prevents the disease or reduces it.7[39] 4 – 5 (rat)[40] Uric acid Water 200 – 400[41] 1.[48] but in humans and most higher primates. while the mechanism of UA as an antioxidant is well-supported. UA has the highest concentration of any blood antioxidant[41] and provides over half of the total antioxidant capacity of human serum.[47] In almost all land animals. [54] In animal studies that investigate diseases facilitated by oxidative stress. total carotenoids)[44] α-Tocopherol (vitamin E) Ubiquinol (coenzyme Q) [edit]Uric Lipid Lipid 10 – 40[43] 5[45] 50 (human)[37] 200 (human)[46] acid Uric acid is by-far the highest concentration antioxidant in human blood.[56] With respect to multiple sclerosis.[59][60] and requires more research.[55] Studies of UA's antioxidant mechanism support this proposal.[50][51] The antioxidant effects of uric acid have led researchers to suggest this mutation was beneficial to early primates and humans[51][52][53] Studies of high altitude acclimatization support the hypothesis that urate acts as an antioxidant by mitigating the oxidative stress caused by high-altitude hypoxia. given that it does not . urate oxidase further catalyzes the oxidation of uric acid to allantoin. Uric acid (UA) is an antioxidant oxypurine produced from xanthine by the enzyme xanthine oxidase. Likewise. the urate oxidase gene is nonfunctional. and is an intermediate product of purine metabolism.Lipoic acid Water 0.1 – 0.5 – 1[42] retinol (vitamin A): 1 – 3[43] 5 (human. so that UA is not further broken down. In other cells. such as superoxide.[54][62] and some found antioxidant activity at levels as high as 285 μmol/L.) stroke.react with some oxidants.[73][74] Ascorbic acid is a redox catalyst which can reduce.[62][66][67] Conversely. but does act against peroxynitrite.[64] Many of these aforementioned studies determined UA's antioxidant actions within normal physiological levels.[77] [edit]Glutathione . which can be catalysed by protein disulfide isomerase and glutaredoxins. and hypochlorous acid. UA-related risk of gout at high levels (415–530 μmol/L) is only 0. and thereby neutralize.[75] In addition to its direct antioxidant effects. it is therefore a vitamin.[71] Most other animals are able to produce this compound in their bodies and do not require it in their diets.5% per year at UA supersaturation levels (535+ μmol/L). As one of the enzymes needed to make ascorbic acid has been lost bymutation during primate evolution. ischemic stroke. the presence of high levels of the potent antioxidant uric acid in primates (but not other mammals) does not leave much "therapeutic room" for similarly acting extracellular antioxidant drugs to work. ascorbic acid is also a substrate for the redox enzyme ascorbate peroxidase. it is maintained in its reduced form by reaction with glutathione.[69][70] [edit]Ascorbic acid Ascorbic acid or "vitamin C" is a monosaccharide oxidation-reduction (redox) catalyst found in both animals and plants. humans must obtain it from the diet.g. with some studies linking higher levels of uric acid with increased mortality[66][67] and other studies showing no association.[76] Ascorbic acid is present at high levels in all parts of plants and can reach concentrations of 20 millimolar in chloroplasts. reactive oxygen species such as hydrogen peroxide.[62] peroxides. This might be due to uric acid being activated as a defense mechanism against oxidative stress.[65] The effects of uric acid in conditions such as atherosclerosis. and heart attacks are still not well understood.[72] Ascorbic acid is required for the conversion of the procollagen to collagen by oxidizing proline residues to hydroxyproline.[62] As Proctor first noted[68] over two decades ago "the well-established association between high urate levels and atherosclerosis could be a protective reaction (antioxidant) or a primary cause (pro-oxidant)".5% per year with an increase to 4. but instead acting as a pro-oxidant in cases where metabolic derangements shift its production well outside of normal levels.[47] Concerns over elevated UA's contribution to gout must be considered as one of many risk factors. This may account for the repeated failure of human trials of antioxidant agents following successful animal studies in (e. a function that is particularly important in stress resistance in plants.[63] By itself. Melatonin. α-tocopherol has been most studied as it has the highest bioavailability. glutathione peroxidases and glutaredoxins. with the body preferentially absorbing and metabolising this form.[80][81] or by trypanothione in the Kinetoplastids.[73] Due to its high concentration and its central role in maintaining the cell's redox state. which is the ability of a molecule to undergo repeated reduction and oxidation.[79] Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibly oxidized and reduced. once oxidized. [85] Unlike other antioxidants.[78] It is not required in the diet and is instead synthesized in cells from its constituent amino acids. In cells.[87][90] This removes the free radical intermediates and prevents the propagation reaction from .[89] It has been claimed that the α-tocopherol form is the most important lipid-soluble antioxidant.The free radical mechanism of lipid peroxidation. Glutathione is a cysteine-containing peptide found in most forms of aerobic life.[87][88] Of these. as well as reacting directly with oxidants. it has been referred to as a terminal (or suicidal) antioxidant. such as ascorbate in the glutathione-ascorbate cycle. bacillithiol in someGram-positive bacteria. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants and promote free radical formation. and that it protects membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction. Therefore. cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. such as by mycothiol in the Actinomycetes. melatonin does not undergo redox cycling. which are fatsoluble vitamins with antioxidant properties.[84] Melatonin easily crosses cell membranes and the blood–brain barrier. glutathione is maintained in the reduced form by the enzyme glutathione reductase and in turn reduces other metabolites and enzyme systems.[78] In some organisms glutathione is replaced by other thiols. glutathione is one of the most important cellular antioxidants.[86] [edit]Tocopherols and tocotrienols (vitamin E) Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols.[82] [83] [edit]Melatonin Melatonin is a powerful antioxidant. Besides ascorbate. retinol or ubiquinol. medically important conditional prooxidants include uric acid and sulfhydryl amino acids such as homocysteine.[99][100] 2 Fe3+ + Ascorbate → 2 Fe2+ + Dehydroascorbate 2 Fe2+ + 2 H2O2 → 2 Fe3+ + 2 OH· + 2 OH− The relative importance of the antioxidant and pro-oxidant activities of antioxidants are an area of current research.[106] Recent experimental evidence strongly suggests that . less data is available for other dietary antioxidants. This reaction produces oxidised α-tocopheroxyl radicals that can be recycled back to the active reduced form through reduction by other antioxidants. [edit]Potential of antioxidant supplements to damage health Some antioxidant supplements may promote disease and increase mortality in humans.[95][96] The functions of the other forms of vitamin E are even less well-understood.[91] This is in line with findings showing that α-tocopherol. vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide. with this molecule having no significant role in antioxidant metabolism.[89] and tocotrienols may be important in protecting neurons from damage. although γ-tocopherol is anucleophile that may react with electrophilic mutagens.continuing. That is. paradoxically. the pathogenesis of diseases involving hyperuricemia likely involve uric acid's direct and indirect pro-oxidant properties. The potential role of the pro-oxidant role of uric acid in (e. agents which are normally considered antioxidants can act as conditional prooxidants and actually increase oxidative stress. For example.[103][104] Likewise. appears to have a mostly antioxidant action in the human body.) atherosclerosis and ischemic stroke is considered above. such as vitamin E. free radicals induce an endogenous response which protects against exogenous radicals (and possibly other toxic compounds).[97] [edit]Pro-oxidant activities Further information: Pro-oxidant Antioxidants that are reducing agents can also act as pro-oxidants. the roles and importance of the various forms of vitamin E are presently unclear. which exerts its effects as a vitamin by oxidizing polypeptides. However.[98] however. Typically. efficiently protects glutathione peroxidase 4 (GPX4)-deficient cells from cell death. but vitamin C.[104] [105] Hypothetically.[99][101] However. but not water-soluble antioxidants.g.[92] GPx4 is the only known enzyme that efficiently reduces lipid-hydroperoxides within biological membranes. this involves some transition-series metal such as copper or iron as catalyst.[102] or the polyphenols. it will also reduce metal ions that generate free radicals through the Fenton reaction. such as ascorbate. Another example is the postulated role of homocysteine in atherosclerosis.[93][94] and it has even been suggested that the most important function of α-tocopherol is as a signaling molecule. [107] Most importantly. since mice lacking this enzyme die soon after birth.this is indeed the case.[109][110] SOD enzymes are present in almost all aerobic cells and in extracellular fluids. and that such induction of endogenous free radical production extends the life span of Caenorhabditis elegans. manganese or iron.[108][114] In plants.[1][13] Here.[112] The mitochondrial isozyme seems to be the most biologically important of these three. In humans.[115] Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen. As with antioxidant metabolites. this induction of life span is prevented by antioxidants. the superoxide released by processes such as oxidative phosphorylation is first converted to hydrogen peroxide and then further reduced to give water.[108] [edit]Superoxide dismutase. providing direct evidence that toxic radicals may mitohormetically exert life extending and health promoting effects.[110] There also exists a third form of SOD in extracellular fluids. zinc. which contains copper and zinc in its active sites. while mice without the extracellular SOD have minimal defects (sensitive to hyperoxia). This detoxification pathway is the result of multiple enzymes. cells are protected against oxidative stress by an interacting network of antioxidant enzymes.[111] Superoxide dismutase enzymes contain metal ion cofactors that. but the generation of transgenic mice lacking just one antioxidant enzyme can be informative. depending on the isozyme.[118] Catalase is an unusual enzyme since.[104][105] [edit]Enzyme systems Enzymatic pathway for detoxification of reactive oxygen species. although hydrogen peroxide is its only . [edit]Overview As with the chemical antioxidants. SOD isozymes are present in the cytosol and mitochondria. using either an iron or manganese cofactor.[113] In contrast. can be copper. with superoxide dismutases catalysing the first step and then catalases and various peroxidases removing hydrogen peroxide. the mice lacking copper/zinc SOD (Sod1) are viable but have numerous pathologies and a reduced lifespan (see article on superoxide). the contributions of these enzymes to antioxidant defenses can be hard to separate from one another. the copper/zinc SOD is present in the cytosol. catalase and peroxiredoxins Superoxide dismutases (SODs) are a class of closely related enzymes that catalyze the breakdown of the superoxide anion into oxygen and hydrogen peroxide.[116][117] This protein is localized to peroxisomes in most eukaryotic cells. with an iron SOD found in chloroplasts that is absent from vertebrates andyeast. while manganese SOD is present in the mitochondrion. a bacterial2-cysteine peroxiredoxin from Salmonella typhimurium. atypical 2-cysteine peroxiredoxins. organic hydroperoxides. that can cycle between an active dithiol form (reduced) and an oxidizeddisulfide form.substrate. [126] Peroxiredoxins seem to be important in antioxidant metabolism. humans with genetic deficiency of catalase — "acatalasemia" — or mice genetically engineered to lack catalase completely.[125] Over-oxidation of this cysteine residue in peroxiredoxins inactivates these enzymes.[124] These enzymes share the same basic catalytic mechanism. its cofactor is oxidised by one molecule of hydrogen peroxide and then regenerated by transferring the bound oxygen to a second molecule of substrate. while plants use peroxiredoxins to remove hydrogen peroxide generated in chloroplasts. in which a redox-active cysteine (the peroxidatic cysteine) in the active site is oxidized to a sulfenic acid by the peroxide substrate.[120][121] Decameric structure of AhpC. such as Arabidopsis thaliana.[133] . as mice lacking peroxiredoxin 1 or 2 have shortened lifespan and suffer from hemolytic anaemia. and 1-cysteine peroxiredoxins. it follows a ping-pong mechanism.[127][128][129] [edit]Thioredoxin and glutathione systems The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase. scavenging reactive oxygen species and maintaining other proteins in their reduced state.[123] They are divided into three classes: typical 2-cysteine peroxiredoxins. thioredoxin acts as an efficient reducing agent. as well as peroxynitrite. using NADPH as an electron donor. have a particularly great diversity of isoforms. In its active state.[131] The active site of thioredoxin consists of two neighboring cysteines. the active thioredoxin is regenerated by the action of thioredoxin reductase. as part of a highly conserved CXXC motif. [132] After being oxidized. [119] Despite its apparent importance in hydrogen peroxide removal. Here. Plants.[122] Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide. but this can be reversed by the action ofsulfiredoxin. suffer few ill effects. [130] Proteins related to thioredoxin are present in all sequenced organisms. antioxidant vitamin supplementation has no detectable effect on the aging process.[135] Glutathione peroxidase 1 is the most abundant and is a very efficient scavenger of hydrogen peroxide.[78] This system is found in animals. the glutathione S-transferases show high activity with lipid peroxides.[149] A low calorie diet extends median and maximum lifespan in many animals. which results in atherosclerosis. Surprisingly. Here. glutathione S-transferase etc.[143] [144] rheumatoid arthritis. and finally cardiovascular disease. Oxidative stress Oxidative stress is thought to contribute to the development of a wide range of diseases including Alzheimer's disease. catalase. glutathione peroxidase.[147][148] Oxidative damage in DNA can cause cancer.[153][154][155] Indeed.[140][141] Parkinson's disease. while glutathione peroxidase 4 is most active with lipid hydroperoxides. glutathione peroxidases and glutathione S-transferases. glutathione peroxidase 1 is dispensable.[157][158] One reason for this might be the fact that consuming antioxidant molecules such as polyphenols and vitamin E will produce changes in other parts . There are at least four different glutathione peroxidase isozymes in animals.[137] In addition.[142] the pathologies caused bydiabetes.[146] In many of these cases.[156] Diets high in fruit and vegetables. protect DNA from oxidative stress. This effect may involve a reduction in oxidative stress.[139] [edit]Oxidative stress in disease Further information: Pathology.[138] These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism. so the effects of fruit and vegetables may be unrelated to their antioxidant contents. glutathione reductase. it is unclear if oxidants trigger the disease. Free-radical theory of aging. Several antioxidant enzymes such as superoxide dismutase.[151][152] the evidence in mammals is less clear. low density lipoprotein (LDL) oxidation appears to trigger the process of atherogenesis. a 2009 review of experiments in mice concluded that almost all manipulations of antioxidant systems had no effect on aging. which are high in antioxidants. or if they are produced as a secondary consequence of the disease and from general tissue damage.[136] but they are hypersensitive to induced oxidative stress. glutathione reductase.[150] While there is some evidence to support the role of oxidative stress in aging in model organisms such as Drosophila melanogaster and Caenorhabditis elegans. plants and microorganisms.[16] One case in which this link is particularly well-understood is the role of oxidative stress in cardiovascular disease. as mice lacking this enzyme have normal lifespans.[78][134] Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyzes the breakdown of hydrogen peroxide and organic hydroperoxides. It has been proposed that polymorphisms in these enzymes are associated with DNA damage and subsequently the individual’s risk of cancer susceptibility.[145] and neurodegeneration in motor neuron diseases.The glutathione system includes glutathione. promote health and reduce the effects of aging. [170][172] This suggests that these health benefits come from other substances in fruits and vegetables (possibly dietary fiber) or come from a complex mix of compounds. Here.[161] sodium thiopental and propofol are used to treat reperfusion injury and traumatic brain injury. and fruits in general. superoxide dismutase mimetics. Mitochondria-targeted ubiquinone. the antioxidant effect of flavonoid-rich foods seems to be due to fructose-induced increases in the synthesis of the antioxidant uric acid and not to dietary antioxidants per se. These compounds appear to prevent oxidative stress in neurons and prevent apoptosis and neurological damage. for example. antioxidants are commonly used as medications to treat various forms of brain injury.of metabolism.[162] while the experimental drugs disufenton sodium[163][164] and ebselen[165] are being applied in the treatment of stroke. and amyotrophic lateral sclerosis. this suggested that antioxidant compounds might lower risk against several diseases.[166][167] and as a way to prevent noise-induced hearing loss.[171] Since fruits and vegetables happen to be good sources of nutrients andphytochemicals.[95][159] [edit]Potential [edit]Organ health effects function The brain is uniquely vulnerable to oxidative injury.[169] [edit]Relation to diet Structure of resveratrol under study for its potential as a dietary antioxidant People who eat fruits and vegetables have a lower risk of heart disease and some neurological diseases. may prevent damage to the liver caused by excessive alcohol. the target of lipid peroxidation. Antioxidants are also being investigated as possible treatments for neurodegenerative diseases such as Alzheimer's disease. and it may be these other effects that are the real reason these compounds are important in human nutrition. This idea has been tested in a limited manner inclinical trials and does not seem to be true. as antioxidant supplements have no clear effect on the risk of chronic diseases such as cancer and heart disease.[173] For example. may lower risk against some cancers. [170] and there is evidence that some types of vegetables. due to its high metabolic rate and elevated levels of polyunsaturated lipids.[174] . Parkinson's disease.[160] Consequently.[168] Targeted antioxidants may lead to better medicinal effects. [184] Rather.[180][181] While several trials have investigated supplements with high doses of antioxidants. especially of beta carotene.[170][172][183] Indeed.500 French men and women took either low-dose antioxidants (120 mg of ascorbic acid.[190] This leads to a large increase in the production of oxidants and results in damage that contributes to muscular fatigue during .[182] Over 12. inflammatory enzyme activity or gene regulation. and 20 mg of zinc) or placebo pills for an average of 7. the "Supplémentation en Vitamines et Mineraux Antioxydants" (SU. controlled studies using antioxidant vitamins have observed no reduction in either the risk of developing heart disease. despite the clear role of oxidative stress in cardiovascular disease. The study concluded that low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. [179] Overall. in doses ranging from 50 to 600 mg per day. some authors argue that the hypothesis that antioxidants could prevent chronic diseases has now been disproved and that the idea was misguided from the beginning. dietary polyphenols may have non-antioxidant roles in minute concentrations that affect cell-to-cell signaling.5 years.[153][154][155] Nevertheless. 6 mgof beta carotene. there is considerable doubt as to whether antioxidant supplements are beneficial or harmful. at least seven large clinical trials were conducted to test the effects of antioxidant supplement with Vitamin E. oxygen consumption can increase by a factor of more than 10. and if they are actually beneficial. and initial observational studies found that people taking Vitamin E supplements had a lower risk of developing heart disease.[188] and the situation in mammals is even less clear.[175] Consequently. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants. 30 mg of vitamin E. it has even been suggested that moderate levels of oxidative stress may increase lifespan in the worm Caenorhabditis elegans. None of these trials found a statistically significant effect of Vitamin E on overall number of deaths or on deaths due to heart disease.VI. antioxidant supplements do not appear to increase life expectancy in humans.[187] The suggestion that increased life expectancy comes from increased oxidative stress conflicts with results seen in the yeast Saccharomyces cerevisiae. 100 µg of selenium.[176] Further studies have also been negative.[185][186] For overall life expectancy.[189] [edit]Physical exercise During exercise. which antioxidant(s) are needed and in what amounts. by inducing a protective response to increased levels of reactive oxygen species. or the rate of progression of existing disease.It is thought that oxidation of low density lipoprotein in the blood contributes to heart disease.MAX) study tested the effect of supplementation with doses comparable to those in a healthy diet.[177][178] 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. receptor sensitivity. Although some levels of antioxidant vitamins and minerals in the diet are required for good health. [192] The evidence for benefits from antioxidant supplementation in vigorous exercise is mixed. 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. which is the period during which most of the adaptation that leads to greater fitness occurs. and some research suggests that supplementation with amounts as high as 1000 mg inhibits recovery.[199] A review published in Sports Medicine looked at 150 studies on antioxidant supplementation during exercise.[191] Antioxidant supplements may also prevent any of the health gains that normally come from exercise.[193] This effect may be to some extent protective against diseases which are associated with oxidative stress. especially in the 24 hours after an exercise session.[196] Although there appears to be no increased requirement for vitamin C in athletes. such as increased insulin sensitivity. The review found that even studies that found a reduction in oxidative stress failed to demonstrate benefits to performance or prevention of muscle damage. There is strong evidence that one of the adaptations resulting from exercise is a strengthening of the body's antioxidant defenses. As a result. which would provide a partial explanation for the lower incidence of major diseases and better health of those who undertake regular exercise.and after exercise.[194] No benefits for physical performance to athletes are seen with vitamin E supplementation. excessive antioxidant levels may inhibit recovery and adaptation mechanisms. free radicals are produced by neutrophils to remove damaged tissue. particularly the glutathione system.[197][198] Other studies found no such effects. During this process. despite its key role in preventing lipid membrane peroxidation. The immune system response to the damage done by exercise peaks 2 to 7 days after exercise. 6 weeks of vitamin E supplementation had no effect on muscle damage in ultramarathon runners. to regulate the increased oxidative stress.[195] Indeed.[200] [edit]Adverse effects . The inflammatory response that occurs after strenuous exercise is also associated with oxidative stress. Some studies indicated that antioxidant supplementation could work against the cardiovascular benefits of exercise. vitamin A or vitamin E supplementation is associated with increased mortality but saw no significant effect from vitamin C.[210] These harmful effects may also be seen in non-smokers.[205] Phytic acid Tea. confirming the previous results.[213] and that antioxidant supplements increased the risk of colon cancer.000 patients showed that β-carotene. 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.[214] However. As the majority of these low-bias trials dealt with either elderly people. tannins and phytic acid.[203] Foods Reducing acid present Cocoa bean and chocolate.[207] Toxicity associated with high doses of watersoluble antioxidants such as ascorbic acid are less of a concern.[211] This meta-analysis was later repeated and extended by the same authors. these results may not apply to the general population.[202] Calciumand iron deficiencies are not uncommon in diets in developing countries where less meat is eaten and there is high consumption of phytic acid from beans and unleavened whole grain bread. legumes. very high doses of some antioxidants may have harmful long-term effects. maize. but an increase in mortality was detected only when the high-quality and low-bias risk trials were examined separately. turnip and rhubarb. or people already suffering disease.[208] More seriously. with the new analysis published by the Cochrane Collaboration. as these compounds can be excreted rapidly in urine. the results of this meta-analysis are inconsistent with other studies such as . which are high in plant-based diets. spinach.[204][206] Tannins Nonpolar antioxidants such as eugenol—a major component of oil of cloves—have toxicity limits that can be exceeded with the misuse of undilutedessential oils. [209] Subsequent studies confirmed these adverse effects.Structure of the metal chelator phytic acid. [212] These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality.[105] No health risk was seen when all the randomized controlled studies were examined together.[204] Oxalic acid Whole grains. as a recent meta-analysis including data from approximately 230. beans. Relatively strong reducing acids can have antinutrient effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed.[201] Notable examples are oxalic acid. cabbage. eggs. making these cells more susceptible to the further oxidative stress induced by treatments. legumes and nuts. grain cereals.the SU.[182][215][216] [217] Overall.[225] Antioxidants are found in varying amounts in foods such as vegetables. such as the . it has been proposed that antioxidants may. the large number of clinical trials carried out on antioxidant supplements suggest that either these products have no effect on health. and the Trolox equivalent antioxidant capacity assay. antioxidant supplements could decrease the effectiveness of radiotherapy and chemotherapy. other reviews have suggested that antioxidants could reduce side effects or increase survival times. which suggested that antioxidants have no effect on cause-all mortality.[219][220] On the other hand.[218] This was thought to occur since the environment of cancer cells causes high levels of oxidative stress.[223][224] Other measurement tests include the Folin-Ciocalteu reagent. juices and food additives. Measurement of antioxidants is not a straightforward process.[221][222] [edit]Measurement and levels in food Further information: List of antioxidants in food.[105][170][172] While antioxidant supplementation is widely used in attempts to prevent the development of cancer. interfere with cancer treatments. the oxygen radical absorbance capacity (ORAC) has become the current industry standard for assessing antioxidant strength of whole foods. In food science.VI. Some antioxidants such aslycopene and ascorbic acid can be destroyed by long-term storage or prolonged cooking. Polyphenol antioxidants Fruits and vegetables are good sources of antioxidants. by reducing the redox stress in cancer cells. paradoxically. as this is a diverse group of compounds with different reactivities to different reactive oxygen species. fruits. or that they cause a small increase in mortality in elderly or vulnerable populations. meat.[226][227] Other antioxidant compounds are more stable.MAX trial. As a result. even large oral doses have little effect on the concentration of glutathione in the body.[46] Another example is glutathione. ubiquinol (coenzyme Q) is poorly absorbed from the gut and is made in humans through the mevalonate pathway. or even kill existing cancer cells.[228][229] The effects of cooking and food processing are complex. such as acute respiratory distress syndrome. olive oil.polyphenolic antioxidants in foods such as whole-wheat cereals and tea.[230] In general. carotenes. which is made from amino acids.[184] Some of these compounds. coffee. vegetables and eggs. cinnamon. chocolate. which the body responds to by inducing higher levels of antioxidant defenses such as antioxidant enzymes. or preventing the liver damage produced by paracetamol overdose.[238]Supplying more of these precursors may be useful as part of the treatment of some diseases. may be chemopreventive agents that either block the transformation of abnormal cells into cancerous cells. oregano Carotenoids (lycopene. consuming the compound causes oxidative stress. Here. protein-energy malnutrition.[231] Antioxidant compounds Foods containing high levels of these antioxidants[206] [232][233] Vitamin C (ascorbic acid) Fresh Fruits and vegetables Vitamin E (tocopherols. such as isothiocyanates and curcumin. tocotrienols) Vegetable oils Polyphenolic antioxidants (resveratrol. since the preparation processes may expose the food to oxygen.[234] Other antioxidants are not vitamins and are instead made in the body. flavonoids) Tea. lutein) Fruit. fruit. such as some carotenoids in vegetables. as these processes can also increase the bioavailability of antioxidants. soy.[184][240] [edit]Uses [edit]Food in technology preservatives . processed foods contain fewer antioxidants than fresh and uncooked foods.[235][236] Although large amounts of sulfur-containing amino acids such as acetylcysteine can increase glutathione. glycine and glutamic acid before being absorbed. For example. As any glutathione in the gut is broken down to free cysteine.[237] no evidence exists that eating high levels of these glutathione precursors is beneficial for healthy adults.[237][239] Other compounds in the diet can alter the levels of antioxidants by acting as pro-oxidants. it is important to avoid oxidation in fat-rich foods. storing plant materials in anaerobic conditions produces unpleasant flavors and unappealing colors. instead. tertiary butylhydroquinone (TBHQ).[248] They are widely used to prevent the oxidative degradation of polymers such as rubbers. and in gasolines to prevent the polymerization that leads to the formation of engine-fouling residues. The mode of cracking varies between oxygen and ozone attack. these foods are rarely preserved by drying. which is why fats such as butter should never be wrapped in aluminium foil or kept in metal containers.[246] Antioxidant preservatives are also added to fatbased cosmetics such as lipstick and moisturizers to prevent rancidity.[245] Since oxidized lipids are often discolored and usually have unpleasant tastes such as metallic or sulfurous flavors. as with cucumbers. butylated hydroxyanisole (BHA. are especially susceptible to oxidation and ozonolysis. Oxidation and UV degradation are also frequently linked. Even less fatty foods such as fruits are sprayed with sulfurous antioxidants prior to air drying. mainly because UV radiation creates free radicals by bond . oxidation reactions still occur relatively rapidly in frozen or refrigerated food. This created a revenue of circa 3. packaging of fresh fruits and vegetables contains an ~8% oxygen atmosphere. A common use is as stabilizers in fuels and lubricants to prevent oxidation. However. They can be protected by antiozonants. as well as synthetic antioxidants such as propyl gallate (PG.[241] Consequently. plastics and adhesives that causes a loss of strength and flexibility in these materials.[247] In 2007. oxidation causes them to turn rancid.Antioxidants are used as food additives to help guard against food deterioration. E320) and butylated hydroxytoluene (BHT. Exposure to oxygen and sunlight are the two main factors in the oxidation of food. but remain sensitive to photooxidation. while ozone attack produces deeper cracks aligned at right angles to the tensile strain in the product.4 billion Euros). E321). Solid polymer products start to crack on exposed surfaces as the material degrades and the chains break. Antioxidants are an especially important class of preservatives as.[242] These preservatives include natural antioxidants such as ascorbic acid (AA.88 million tons. the worldwide market for industrial antioxidants had a total volume of around 0. Oxidation is often catalyzed by metals.[249] Polymers containing double bonds in their main chains. E300) and tocopherols (E306). as oxygen is also important for plant respiration. Some fatty foods such as olive oil are partially protected from oxidation by their natural content of antioxidants. unlike bacterial or fungal spoilage. the former causing a "crazy paving" effect. they are preserved by smoking. salting orfermenting.7 billion USdollars (2. so food is preserved by keeping in the dark and sealing it in containers or even coating it in wax. Thus. [edit]Industrial uses Antioxidants are frequently added to industrial products. E310). such as natural rubber and polybutadiene.[243][244] The most common molecules attacked by oxidation are unsaturated fats. breakage. hydraulic fluids. and greases AO-24 N. Attack occurs at this point because the free radical formed is more stable than one formed on a primary carbon atom. Other polymers susceptible to oxidation include polypropylene and polyethylene. including aviation gasolines AO-32 2. waxes. widely approved for aviation fuels also Pharmacy and Pharmacology portal   Forensic engineering Mitohormesis – Hormesis . transformer oils.4-phenylenediamine Low-temperature oils AO-29 2.N'-di-2-butyl-1. and gasolines AO-30 2.4-dimethyl-6-tert-butylphenol Jet fuels and gasolines.N'-di-2-butyl-1.4-dimethyl-6-tert-butylphenol and 2. including aviation gasolines AO-37 [edit]See 2. waxes.4-phenylenediamine Turbine oils. The former is more sensitive owing to the presence of secondary carbon atoms present in every repeat unit. Fuel additive Components[250] Applications[250] AO-22 N.6-ditert-butyl-4-methylphenol Jet fuels and gasolines. often in a chain reaction. greases.4-dimethyl-6-tert-butylphenol Jet fuels and gasolines. transformer oils. such as branch points in low density polyethylene. including aviation gasolines AO-31 2.6-di-tert-butyl-4-methylphenol Turbine oils. The free radicals then react with oxygen to produce peroxy radicals which cause yet further damage. hydraulic fluids.6-di-tert-butylphenol Jet fuels and gasolines. Oxidation of polyethylene tends to occur at weak links in the chain. doi:10..297. PMID 10335367. "Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis". PMID 9846200.. Gluud.doi:10. Helmut (1997). Annual Review of Biochemistry 16: 177– 92.1146/annurev.. "Oxidative stress: Oxidants and antioxidants". MacNee. 5. "Free radicals: Their history and current status in aging and disease". 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