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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 as thiols, 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 of phenylenediamine 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. Low 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 trials with a limited number of antioxidants detect 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.

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 angiosperm plants 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][7] 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 polymerization of fuels in the fouling of internal combustion engines.[8]

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.[9] 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.[10][11]

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.[12] 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.[13]

The oxidative challenge in biology

Further information: Oxidative stress
The structure of the antioxidant vitamin ascorbic 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.[14] Consequently, organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids.[1][15] 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][14] 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.[16]

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−).[17] 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.[18] 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,[19][20] while damage to proteins causes enzyme inhibition, denaturation and protein degradation.[21]

The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.[22] In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.[23] 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 well-controlled reactions of the electron transport chain.[24] Peroxide is also produced from the oxidation of reduced flavoproteins, such as complex I.[25] However, although these enzymes can produce oxidants, the relative importance of the electron transfer chain to other processes that generate peroxide is unclear.[26][27] In plants, algae, and cyanobacteria, reactive oxygen species are also produced during photosynthesis,[28] particularly under conditions of high light intensity.[29] This effect is partly offset by the involvement of carotenoids in photoinhibition, which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species.[30][31]

Metabolites

Overview

Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytosol and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation.[1] These compounds may be synthesized in the body or obtained from the diet.[15] 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). Some antioxidants are only found in a few organisms and these compounds can be important in pathogens and can be virulence factors.[32]

The relative importance and interactions between these different antioxidants is a very complex question, with the various metabolites and enzyme systems having synergistic and interdependent effects on one another.[33][34] The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system.[15] 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.[15]

Some compounds contribute to antioxidant defense by chelating transition metals and preventing them from catalyzing the production of free radicals in the cell. Particularly important is the ability to sequester iron, which is the function of iron-binding proteins such as transferrin and ferritin.[27] Selenium and zinc are commonly referred to as antioxidant nutrients, but these chemical elements have no antioxidant action themselves and are instead required for the activity of some antioxidant enzymes, as is discussed below.

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] 6,400 (human)[37]
Lipoic acid Water 0.1 – 0.7[39] 4 – 5 (rat)[40]
Uric acid Water 200 – 400[41] 1,600 (human)[37]
Carotenes Lipid β-carotene: 0.5 – 1[42]

retinol (vitamin A): 1 – 3[43]

5 (human, total carotenoids)[44]
α-Tocopherol (vitamin E) Lipid 10 – 40[43] 50 (human)[37]
Ubiquinol (coenzyme Q) Lipid 5[45] 200 (human)[46]

Uric acid

Uric acid is by-far the highest concentration antioxidant in human blood. Uric acid (UA) is an antioxidant oxypurine produced from xanthine by the enzyme xanthine oxidase, and is an intermediate product of purine metabolism.[47] In almost all land animals, urate oxidase further catalyzes the oxidation of uric acid to allantoin,[48] but in humans and most higher primates, the urate oxidase gene is nonfunctional, so that UA is not further broken down.[48][49] The evolutionary reasons for this loss of urate converstion to allantoin remain the topic of active speculation.[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.[54] In animal studies that investigate diseases facilitated by oxidative stress, introduction of UA both prevents the disease or reduces it, leading researchers to propose this is due to UA's antioxidant properties.[55] Studies of UA's antioxidant mechanism support this proposal.[56]

With respect to multiple sclerosis, 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. Moreover, the administration of UA is therapeutic in experimental allergic encephalomyelitis (EAE), an animal model of MS."[55][57][58] In sum, while the mechanism of UA as an antioxidant is well-supported, the claim that its levels affect MS risk is still controversial,[59][60] and requires more research.

Likewise, UA has the highest concentration of any blood antioxidant[41] and provides over half of the total antioxidant capacity of human serum.[61] Uric acid's antioxidant activities are also complex, given that it does not react with some oxidants, such as superoxide, but does act against peroxynitrite,[62] peroxides, and hypochlorous acid.[47] Concerns over elevated UA's contribution to gout must be considered as one of many risk factors.[63] By itself, UA-related risk of gout at high levels (415–530 μmol/L) is only 0.5% per year with an increase to 4.5% per year at UA supersaturation levels (535+ μmol/L).[64] Many of these aforementioned studies determined UA's antioxidant actions within normal physiological levels,[54][62] and some found antioxidant activity at levels as high as 285 μmol/L.[65]

The effects of uric acid in conditions such as atherosclerosis, ischemic stroke, and heart attacks are still not well understood, with some studies linking higher levels of uric acid with increased mortality[66][67] and other studies showing no association.[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)". This might be due to uric acid being activated as a defense mechanism against oxidative stress, but instead acting as a pro-oxidant in cases where metabolic derangements shift its production well outside of normal levels.[62][66][67] Conversely, 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. This may account for the repeated failure of human trials of antioxidant agents following successful animal studies in (e.g.) stroke.[69][70]

Ascorbic acid

Ascorbic acid or "vitamin C" is a monosaccharide oxidation-reduction (redox) catalyst found in both animals and plants. As one of the enzymes needed to make ascorbic acid has been lost by mutation during primate evolution, humans must obtain it from the diet; 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.[72] Ascorbic acid is required for the conversion of the procollagen to collagen by oxidizing proline residues to hydroxyproline. In other cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by protein disulfide isomerase and glutaredoxins.[73][74] Ascorbic acid is a redox catalyst which can reduce, and thereby neutralize, reactive oxygen species such as hydrogen peroxide.[75] In addition to its direct antioxidant effects, ascorbic acid is also a substrate for the redox enzyme ascorbate peroxidase, a function that is particularly important in stress resistance in plants.[76] Ascorbic acid is present at high levels in all parts of plants and can reach concentrations of 20 millimolar in chloroplasts.[77]

Glutathione

The free radical mechanism of lipid peroxidation.

Glutathione is a cysteine-containing peptide found in most forms of aerobic life.[78] It is not required in the diet and is instead synthesized in cells from its constituent amino acids.[79] 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, such as ascorbate in the glutathione-ascorbate cycle, glutathione peroxidases and glutaredoxins, as well as reacting directly with oxidants.[73] 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.[78] In some organisms glutathione is replaced by other thiols, such as by mycothiol in the Actinomycetes, bacillithiol in some Gram-positive bacteria,[80][81] or by trypanothione in the Kinetoplastids.[82][83]

Melatonin

Melatonin is a powerful antioxidant.[84] Melatonin easily crosses cell membranes and the blood-brain barrier.[85] Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of a molecule to undergo repeated reduction and oxidation. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants 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.[86]

Tocopherols and tocotrienols (vitamin E)

Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols, which are fat-soluble vitamins with antioxidant properties.[87][88] Of these, α-tocopherol has been most studied as it has the highest bioavailability, with the body preferentially absorbing and metabolising this form.[89]

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.[87][90] 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.[91] This is in line with findings showing that α-tocopherol, but not water-soluble antioxidants, efficiently protects glutathione peroxidase 4 (GPX4)-deficient cells from cell death.[92] GPx4 is the only known enzyme that efficiently reduces lipid-hydroperoxides within biological membranes.

However, the roles and importance of the various forms of vitamin E are presently unclear,[93][94] and it has even been suggested that the most important function of α-tocopherol is as a signaling molecule, with this molecule having no significant role in antioxidant metabolism.[95][96] The functions of the other forms of vitamin E are even less well-understood, although γ-tocopherol is a nucleophile that may react with electrophilic mutagens,[89] and tocotrienols may be important in protecting neurons from damage.[97]

Pro-oxidant activities

Further information: 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,[98] however, it will also reduce metal ions that generate free radicals through the Fenton reaction.[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, but vitamin C, which exerts its effects as a vitamin by oxidizing polypeptides, appears to have a mostly antioxidant action in the human body.[99][101] However, less data is available for other dietary antioxidants, such as vitamin E,[102] or the polyphenols.[103][104] Likewise, the pathogenesis of diseases involving hyperuricemia likely involve uric acid's direct and indirect pro-oxidant properties.

That is, paradoxically, agents which are normally-considered antioxidants can act as conditional pro-oxidants and actually increase oxidative stress. Besides ascorbate, medically-important conditional pro-oxidants include uric acid and sulfhydryl amino acids such as homocysteine. Typically, this involves some transition-series metal such as copper or iron as catalyst. The potential role of the pro-oxidant role of uric acid in (e.g.) atherosclerosis and ischemic stroke is considered above. Another example is the postulated role of homocysteine in atherosclerosis.

Potential of antioxidant supplements to damage health

Some antioxidant supplements may promote disease and increase mortality in humans.[104][105] Hypothetically, free radicals induce an endogenous response which protects against exogenous radicals (and possibly other toxic compounds).[106] Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free radical production extends the life span of Caenorhabditis elegans.[107] Most importantly, this induction of life span is prevented by antioxidants, providing direct evidence that toxic radicals may mitohormetically exert life extending and health promoting effects.[104][105]

Enzyme systems

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.[1][14] 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 antioxidant defenses can be hard to separate from one another, but the generation of transgenic mice lacking just one antioxidant enzyme can be informative.[108]

Superoxide dismutase, 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.[109][110] SOD enzymes are present in almost all aerobic cells and in extracellular fluids.[111] 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.[110] There also exists a third form of SOD in extracellular fluids, which contains copper and zinc in its active sites.[112] The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth.[113] In contrast, the mice lacking copper/zinc SOD (Sod1) are viable but have numerous pathologies and a reduced lifespan (see article on superoxide), while mice without the extracellular SOD have minimal defects (sensitive to hyperoxia).[108][114] In plants, SOD isozymes are present in the cytosol and mitochondria, with an iron SOD found in chloroplasts that is absent from vertebrates and yeast.[115]

Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor.[116][117] This protein is localized to peroxisomes in most eukaryotic cells.[118] Catalase is an unusual enzyme since, although hydrogen peroxide is its only substrate, it follows a 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.[119] 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.[120][121]

Decameric structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium.[122]

Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite.[123] They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins.[124] 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.[125] Over-oxidation of this cysteine residue in peroxiredoxins inactivates these enzymes, but this can be reversed by the action of sulfiredoxin.[126] 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.[127][128][129]

Thioredoxin and glutathione systems

The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase.[130] Proteins related to thioredoxin are present in all sequenced organisms. Plants, such as Arabidopsis thaliana, have a particularly great diversity of isoforms.[131] The active site of thioredoxin consists of two neighboring cysteines, as part of a highly conserved CXXC 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.[132] After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using NADPH as an electron donor.[133]

The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases and glutathione S-transferases.[78] This system is found in animals, plants and microorganisms.[78][134] Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyzes the breakdown of hydrogen peroxide and organic hydroperoxides. There are at least four different glutathione peroxidase isozymes in animals.[135] 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,[136] but they are hypersensitive to induced oxidative stress.[137] In addition, the glutathione S-transferases show high activity with lipid peroxides.[138] These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism.[139]

Oxidative stress in disease

Further information: Pathology, Free-radical theory of aging, Oxidative stress

Oxidative stress is thought to contribute to the development of a wide range of diseases including Alzheimer's disease,[140][141] Parkinson's disease,[142] the pathologies caused by diabetes,[143][144] rheumatoid arthritis,[145] and neurodegeneration in motor neuron diseases.[146] In many of these cases, it is unclear if oxidants trigger the disease, or if they are produced as a secondary consequence of the disease and from general tissue damage;[17] 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 atherogenesis, which results in atherosclerosis, and finally cardiovascular disease.[147][148]

Oxidative damage in DNA can cause cancer. Several antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase etc. protect DNA from oxidative stress. It has been proposed that polymorphisms in these enzymes are associated with DNA damage and subsequently the individual’s risk of cancer susceptibility.[149]

A low calorie diet extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress.[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,[151][152] the evidence in mammals is less clear.[153][154][155] Indeed, a 2009 review of experiments in mice concluded that almost all manipulations of antioxidant systems had no effect on aging.[156] Diets high in fruit and vegetables, which are high in antioxidants, promote health and reduce the effects of aging; 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.[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 of metabolism, so it may be these other effects that are the real reason these compounds are important in human nutrition.[95][159]

Potential health effects

Organ function

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.[160] Consequently, antioxidants are commonly used as medications to treat various forms of brain injury. Here, superoxide dismutase mimetics,[161] sodium thiopental and propofol are used to treat reperfusion injury and traumatic brain injury,[162] while the experimental drugs disufenton sodium[163][164] and ebselen[165] 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 Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis,[166][167] and as a way to prevent noise-induced hearing loss.[168] Targeted antioxidants may lead to better medicinal effects. Mitochondria-targeted ubiquinone, for example, may prevent damage to the liver caused by excessive alcohol.[169]

Relation to diet

Structure of the polyphenol antioxidant resveratrol.

People who eat fruits and vegetables have a lower risk of heart disease and some neurological diseases,[170] and there is evidence that some types of vegetables, and fruits in general, may lower risk against some cancers.[171] Since fruits and vegetables happen to be good sources of nutrients and phytochemicals, this suggested that antioxidant compounds might lower risk against several diseases. This idea has been tested in a limited manner in clinical 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.[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.[173] For example, 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.[174]

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.[175] 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 600 mg per day. None of these trials found a statistically significant effect of Vitamin E on overall number of deaths or on deaths due to heart disease.[176] Further studies have also been negative.[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.[179] Overall, 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.[180][181]

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.[182] Over 12,500 French men and women took either low-dose antioxidants (120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 µg of selenium, and 20 mg of zinc) or placebo pills for an average of 7.5 years. The study concluded that low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene.

Many nutraceutical and health food companies sell formulations of antioxidants as dietary supplements and these are widely used in industrialized countries.[183] These supplements may include specific antioxidant chemicals, like the polyphenol, resveratrol (from grape seeds or knotweed roots),[184] combinations of antioxidants, like the "ACES" products that contain beta carotene (provitamin A), vitamin C, vitamin E and Selenium, or herbs that contain antioxidants – such as green tea, jiaogulan and rooibos tea. Although some levels of antioxidant vitamins and minerals in the diet are required for good health, there is considerable doubt as to whether these antioxidant supplements are beneficial or harmful, and if they are actually beneficial, which antioxidant(s) are needed and in what amounts.[170][172][185] Indeed, 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.[186] Rather, dietary polyphenols may have non-antioxidant roles in minute concentrations that affect cell-to-cell signaling, receptor sensitivity, inflammatory enzyme activity or gene regulation.[187][188]

For overall life expectancy, it has even been suggested that moderate levels of oxidative stress may increase lifespan in the worm Caenorhabditis elegans, by inducing a protective response to increased levels of reactive oxygen species.[189] The suggestion that increased life expectancy comes from increased oxidative stress conflicts with results seen in the yeast Saccharomyces cerevisiae,[190] and the situation in mammals is even less clear.[153][154][155] Nevertheless, antioxidant supplements do not appear to increase life expectancy in humans.[191]

Physical exercise

During exercise, oxygen consumption can increase by a factor of more than 10.[192] 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 the damage done by exercise peaks 2 to 7 days after exercise, which is the period during which most of the adaptation that leads to greater fitness occurs. During this process, free radicals are produced by neutrophils to remove damaged tissue. As a result, excessive antioxidant levels may inhibit recovery and adaptation mechanisms.[193] Antioxidant supplements may also prevent any of the health gains that normally come from exercise, such as increased insulin sensitivity.[194]

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 regulate the increased oxidative stress.[195] 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.[196]

No benefits for physical performance to athletes are seen with vitamin E supplementation.[197] 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.[198] 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.[199][200] Other studies found no such effects, and some research suggests that supplementation with amounts as high as 1000 mg inhibits recovery.[201]

A review published in Sports Medicine looked at 150 studies on antioxidant supplementation during exercise. The review found that even studies that found a reduction in oxidative stress failed to demonstrate benefits to performance or prevention of muscle damage. Some studies indicated that antioxidant supplementation could work against the cardiovascular benefits of exercise.[202]

Adverse effects

Structure of the metal chelator phytic acid.

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.[203] Notable examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets.[204] Calcium and 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.[205]

Foods Reducing acid present
Cocoa bean and chocolate, spinach, turnip and rhubarb.[206] Oxalic acid
Whole grains, maize, legumes.[207] Phytic acid
Tea, beans, cabbage.[206][208] 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 oils.[209] 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.[210] 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.[211] Subsequent studies confirmed these adverse effects.[212]

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.[105] 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. 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.[213] 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.[214] These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality,[215] and that antioxidant supplements increased the risk of colon cancer.[216] 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.[182][217][218][219] 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.[105][170][172]

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.[220] 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 could decrease the effectiveness of radiotherapy and chemotherapy.[221][222] On the other hand, other reviews have suggested that antioxidants could reduce side effects or increase survival times.[223][224]

Measurement and levels in food

Further information: List of antioxidants in food, Polyphenol antioxidants
Fruits and vegetables 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.[225][226] Other measurement tests include the Folin-Ciocalteu reagent, and the Trolox equivalent antioxidant capacity assay.[227]

Antioxidants are found in varying amounts in foods such as vegetables, fruits, grain cereals, eggs, meat, legumes and nuts. Some antioxidants such as lycopene and ascorbic acid can be destroyed by long-term storage or prolonged cooking.[228][229] Other antioxidant compounds are more stable, such as the polyphenolic antioxidants in foods such as whole-wheat cereals and tea.[230][231] The effects of cooking and food processing are complex, as these processes can also increase the bioavailability of antioxidants, such as some carotenoids in vegetables.[232] In general, processed foods contain fewer antioxidants than fresh and uncooked foods, since the preparation processes may expose the food to oxygen.[233]

Antioxidant compounds Foods containing high levels of these antioxidants[208][234][235]
Vitamin C (ascorbic acid) Fresh Fruits and vegetables
Vitamin E (tocopherols, tocotrienols) Vegetable oils
Polyphenolic antioxidants (resveratrol, flavonoids) Tea, coffee, soy, fruit, olive oil, chocolate, cinnamon, oregano and red wine
Carotenoids (lycopene, carotenes, lutein) Fruit, vegetables and eggs.[236]

Other antioxidants are not vitamins and are instead made in the body. For example, ubiquinol (coenzyme Q) is poorly absorbed from the gut and is made in humans through the mevalonate pathway.[46] Another 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.[237][238] Although large amounts of sulfur-containing amino acids such as acetylcysteine can increase glutathione,[239] no evidence exists that eating high levels of these glutathione precursors is beneficial for healthy adults.[240] Supplying more of these precursors may be useful as part of the treatment of some diseases, such as acute respiratory distress syndrome, protein-energy malnutrition, or preventing the liver damage produced by paracetamol overdose.[239][241]

Other compounds in the diet can alter the levels of antioxidants by acting as pro-oxidants. Here, consuming the compound causes oxidative stress, which the body responds to by inducing higher levels of antioxidant defenses such as antioxidant enzymes.[186] Some of these compounds, such as isothiocyanates and curcumin, may be chemopreventive agents that either block the transformation of abnormal cells into cancerous cells, or even kill existing cancer cells.[186][242]

Uses in technology

Food preservatives

Antioxidants are used as food additives to help 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, storing plant materials in anaerobic conditions produces unpleasant flavors and unappealing colors.[243] Consequently, packaging of fresh fruits and vegetables contains an ~8% oxygen atmosphere. Antioxidants are an especially important class of preservatives as, unlike bacterial or fungal spoilage, oxidation reactions still occur relatively rapidly in frozen or refrigerated food.[244] These preservatives include natural antioxidants such as ascorbic acid (AA, E300) and tocopherols (E306), as well as synthetic antioxidants such as propyl gallate (PG, E310), tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA, E320) and butylated hydroxytoluene (BHT, E321).[245][246]

The most common molecules attacked by oxidation are unsaturated fats; oxidation causes them to turn rancid.[247] Since oxidized lipids are often discolored and usually have unpleasant tastes such as metallic or sulfurous 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, salting or 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.[248] Antioxidant preservatives are also added to fat-based cosmetics such as lipstick and moisturizers to prevent rancidity.

Industrial uses

Antioxidants are frequently added to industrial products. A common use is as stabilizers in fuels and lubricants to prevent oxidation, and in gasolines to prevent the polymerization that leads to the formation of engine-fouling residues.[249] In 2007, the worldwide market for industrial antioxidants had a total volume of around 0.88 million tons. This created a revenue of circa 3.7 billion US-dollars (2.4 billion Euros).[250]

They are widely used to prevent the oxidative degradation of polymers such as rubbers, plastics and adhesives that causes a loss of strength and flexibility in these materials.[251] Polymers containing double bonds in their main chains, such as natural rubber and polybutadiene, are especially susceptible to oxidation and ozonolysis. They can be protected by antiozonants. Solid polymer products start to crack on exposed surfaces as the material degrades and the chains break. The mode of cracking varies between oxygen and ozone attack, the former causing a "crazy paving" effect, while ozone attack produces deeper cracks aligned at right angles to the tensile strain in the product. Oxidation and UV degradation are also frequently linked, mainly because UV radiation creates free radicals by bond breakage. The free radicals then react with oxygen to produce peroxy radicals which cause yet further damage, often in a chain reaction. Other polymers susceptible to oxidation include polypropylene and polyethylene. The former is more sensitive owing to the presence of secondary carbon atoms present in every repeat unit. Attack occurs at this point because the free radical formed is more stable than one formed on a primary carbon atom. Oxidation of polyethylene tends to occur at weak links in the chain, such as branch points in low density polyethylene.

Fuel additive Components[252] Applications[252]
AO-22 N,N'-di-2-butyl-1,4-phenylenediamine Turbine oils, transformer oils, hydraulic fluids, waxes, and greases
AO-24 N,N'-di-2-butyl-1,4-phenylenediamine Low-temperature oils
AO-29 2,6-di-tert-butyl-4-methylphenol Turbine oils, transformer oils, hydraulic fluids, waxes, greases, and gasolines
AO-30 2,4-dimethyl-6-tert-butylphenol Jet fuels and gasolines, including aviation gasolines
AO-31 2,4-dimethyl-6-tert-butylphenol Jet fuels and gasolines, including aviation gasolines
AO-32 2,4-dimethyl-6-tert-butylphenol and 2,6-di-tert-butyl-4-methylphenol Jet fuels and gasolines, including aviation gasolines
AO-37 2,6-di-tert-butylphenol Jet fuels and gasolines, widely approved for aviation fuels

See also

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Further reading

  • Nick Lane Oxygen: The Molecule That Made the World (Oxford University Press, 2003) ISBN 0-19-860783-0
  • Barry Halliwell and John M.C. Gutteridge Free Radicals in Biology and Medicine(Oxford University Press, 2007) ISBN 0-19-856869-X
  • Jan Pokorny, Nelly Yanishlieva and Michael H. Gordon Antioxidants in Food: Practical Applications (CRC Press Inc, 2001) ISBN 0-8493-1222-1
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