Model of the antioxidant metaboliteglutathione. 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 can produce free radicals, leading to chain reactions that may damage cells. Antioxidants such as thiols or ascorbic acid (vitamin C) terminate these chain reactions. The term "antioxidant" is mainly used for two different groups of substances: industrial chemicals which are added to products to prevent oxidation, and natural chemicals found in foods and body tissue which are said to have beneficial health effects.
Although certain levels of antioxidant vitamins in the diet are required for good health, there is considerable debate on whether antioxidant-rich foods or supplements have anti-disease activity. Moreover, if they are actually beneficial, it is unknown which antioxidant(s) are needed from the diet and in what amounts beyond typical dietary intake. Some authors dispute the hypothesis that antioxidant vitamins could prevent chronic diseases, while others maintain such a possibility is unproved and misguided from the beginning.
Tirilazad is an antioxidant steroid derivative that inhibits the lipid peroxidation that is believed to play a key role in neuronal death in stroke and head injury. It demonstrated activity in animal models of stroke, but human trials demonstrated no effect on mortality or other outcomes in subarachnoid haemorrhage and worsened results in ischemic stroke.
Similarly, the designed antioxidant NXY-059 exhibited efficacy in animal models, but failed to improve stroke outcomes in a clinical trial. As of November 2014, other antioxidants are being studied as potential neuroprotectants.
Common pharmaceuticals (and supplements) with antioxidant properties may interfere with the efficacy of certain anticancer medication and radiation.
During exercise, oxygen consumption can increase by a factor of more than 10. However, no benefits for physical performance to athletes are seen with vitamin E supplementation and 6 weeks of vitamin E supplementation had no effect on muscle damage in ultramarathon runners. Some research suggests that supplementation with amounts as high as 1000 mg of vitamin C inhibits recovery. Other studies indicated that antioxidant supplementation may attenuate the cardiovascular benefits of exercise.
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. 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. 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. Subsequent studies confirmed these adverse effects.
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. No health risk was seen when all the randomized controlled studies were examined together, but an increase in mortality was detected when only 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 with disease, these results may not apply to the general population. 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. These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality, and that antioxidant supplements increased the risk of colon cancer.Beta-carotene may also increase lung cancer. 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.
While antioxidant supplementation is widely used in attempts to prevent the development of cancer, antioxidants may interfere with cancer treatments, 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 (and pharmaceuticals) could decrease the effectiveness of radiotherapy and chemotherapy. On the other hand, other reviews have suggested that antioxidants could reduce side effects or increase survival times.
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. 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. In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. 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.
The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species. In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain. 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. Peroxide is also produced from the oxidation of reduced flavoproteins, such as complex I. However, although these enzymes can produce oxidants, the relative importance of the electron transfer chain to other processes that generate peroxide is unclear. In plants, algae, and cyanobacteria, reactive oxygen species are also produced during photosynthesis, particularly under conditions of high light intensity. This effect is partly offset by the involvement of carotenoids in photoinhibition, and in algae and cyanobacteria, by large amount of iodide and selenium, which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species.
Antioxidants are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (lipophilic). 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. These compounds may be synthesized in the body or obtained from the diet. 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.
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. The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system. 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.
Some compounds contribute to antioxidant defense by chelatingtransition 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.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.
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. In almost all land animals, urate oxidase further catalyzes the oxidation of uric acid to allantoin, but in humans and most higher primates, the urate oxidase gene is nonfunctional, so that UA is not further broken down. The evolutionary reasons for this loss of urate conversion to allantoin remain the topic of active speculation. The antioxidant effects of uric acid have led researchers to suggest this mutation was beneficial to early primates and humans. Studies of high altitude acclimatization support the hypothesis that urate acts as an antioxidant by mitigating the oxidative stress caused by high-altitude hypoxia.
Uric acid has the highest concentration of any blood antioxidant and provides over half of the total antioxidant capacity of human serum. 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,peroxides, and hypochlorous acid. Concerns over elevated UA's contribution to gout must be considered as one of many risk factors. 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). Many of these aforementioned studies determined UA's antioxidant actions within normal physiological levels, and some found antioxidant activity at levels as high as 285 μmol/L.
Melatonin is a powerful antioxidant. Melatonin easily crosses cell membranes and the blood–brain barrier. 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.
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. 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. 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. 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, 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. 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, and tocotrienols may be important in protecting neurons from damage.
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, however, it will also reduce metal ions that generate free radicals through the Fenton reaction.
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 is 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. However, less data is available for other dietary antioxidants, such as vitamin E, or the polyphenols. 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.
Some antioxidant supplements may promote disease and increase mortality in humans under certain conditions. Hypothetically, free radicals induce an endogenous response that protects against exogenous radicals (and possibly other toxic compounds). Free radicals may increase life span. This increase may be prevented by antioxidants, providing direct evidence that toxic radicals may mitohormetically exert life extending and health promoting effects.
Enzymatic pathway for detoxification of reactive oxygen species.
As with the chemical antioxidants, cells are protected against oxidative stress by an interacting network of antioxidant enzymes. 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.
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. SOD enzymes are present in almost all aerobic cells and in extracellular fluids. 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. There also exists a third form of SOD in extracellular fluids, which contains copper and zinc in its active sites. The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth. 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). 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.
Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor. This protein is localized to peroxisomes in most eukaryotic cells. 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. 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.
Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite. They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins. 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. Over-oxidation of this cysteine residue in peroxiredoxins inactivates these enzymes, but this can be reversed by the action of sulfiredoxin. 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.
The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase. Proteins related to thioredoxin are present in all sequenced organisms. Plants, such as Arabidopsis thaliana, have a particularly great diversity of isoforms. 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. After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using NADPH as an electron donor.
The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases, and glutathione S-transferases. This system is found in animals, plants and microorganisms. 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. 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, but they are hypersensitive to induced oxidative stress. In addition, the glutathione S-transferases show high activity with lipid peroxides. These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism.
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.
Diets high in fruit and vegetables, and so possibly being rich in antioxidant vitamins, have no established effect on status of health or aging, yet may have more subtle physiological effects, such as modifying cell-to-cell communication.
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. 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. 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).
The most common molecules attacked by oxidation are unsaturated fats; oxidation causes them to turn rancid. 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. Antioxidant preservatives are also added to fat based cosmetics such as lipstick and moisturizers to prevent rancidity.
Substituted phenols and derivatives of phenylenediamine are common antioxidants used to inhibit gum formation in gasoline (petrol).
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. In 2014, the worldwide market for natural and synthetic antioxidants was US $2.25 billion with a forecast of growth to $3.25 billion by 2020.
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. 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.
Fruits and vegetables are good sources of antioxidant vitamins A, C and E
Antioxidant vitamins are found in vegetables, fruits, eggs, legumes and nuts. Vitamins A, C, and E can be destroyed by long-term storage or prolonged cooking. 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. Processed food contains fewer antioxidant vitamins than fresh and uncooked foods, as preparation exposes food to heat and oxygen.
Other antioxidants are not obtained from the diet, but instead are made in the body. For example, ubiquinol (coenzyme Q) is poorly absorbed from the gut and is made through the mevalonate pathway. 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 intake has little effect on the concentration of glutathione in the body. Although large amounts of sulfur-containing amino acids such as acetylcysteine can increase glutathione, no evidence exists that eating high levels of these glutathione precursors is beneficial for healthy adults.
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. 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. 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. 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 scavengingreactive oxygen species before they can damage cells.
^Cortés-Jofré M, Rueda JR, Corsini-Muñoz G, Fonseca-Cortés C, Caraballoso M, Bonfill Cosp X (2012). "Drugs for preventing lung cancer in healthy people". The Cochrane Database of Systematic Reviews. 10: CD002141. doi:10.1002/14651858.CD002141.pub2. PMID23076895.
^Jiang L, Yang KH, Tian JH, Guan QL, Yao N, Cao N, Mi DH, Wu J, Ma B, Yang SH (2010). "Efficacy of antioxidant vitamins and selenium supplement in prostate cancer prevention: a meta-analysis of randomized controlled trials". Nutrition and Cancer. 62 (6): 719–27. doi:10.1080/01635581.2010.494335. PMID20661819.
^Rees K, Hartley L, Day C, Flowers N, Clarke A, Stranges S (2013). "Selenium supplementation for the primary prevention of cardiovascular disease". The Cochrane Database of Systematic Reviews. 1 (1): CD009671. doi:10.1002/14651858.CD009671.pub2. PMID23440843.
^ abcStanner SA, Hughes J, Kelly CN, Buttriss J (May 2004). "A review of the epidemiological evidence for the 'antioxidant hypothesis'". Public Health Nutrition. 7 (3): 407–22. doi:10.1079/PHN2003543. PMID15153272.
^Woodside JV, McCall D, McGartland C, Young IS (Nov 2005). "Micronutrients: dietary intake v. supplement use". The Proceedings of the Nutrition Society. 64 (4): 543–53. doi:10.1079/PNS2005464. PMID16313697.
^Virgili F, Marino M (Nov 2008). "Regulation of cellular signals from nutritional molecules: a specific role for phytochemicals, beyond antioxidant activity". Free Radical Biology & Medicine. 45 (9): 1205–16. doi:10.1016/j.freeradbiomed.2008.08.001. PMID18762244.
^Di Matteo V, Esposito E (Apr 2003). "Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis". Current Drug Targets. CNS and Neurological Disorders. 2 (2): 95–107. doi:10.2174/1568007033482959. PMID12769802.
^Crichton GE, Bryan J, Murphy KJ (Sep 2013). "Dietary antioxidants, cognitive function and dementia--a systematic review". Plant Foods for Human Nutrition. 68 (3): 279–92. doi:10.1007/s11130-013-0370-0. PMID23881465.
^Takeda A, Nyssen OP, Syed A, Jansen E, Bueno-de-Mesquita B, Gallo V (2014). "Vitamin A and carotenoids and the risk of Parkinson's disease: a systematic review and meta-analysis". Neuroepidemiology. 42 (1): 25–38. doi:10.1159/000355849. PMID24356061.
^Sena E, Wheble P, Sandercock P, Macleod M (Feb 2007). "Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke". Stroke; A Journal of Cerebral Circulation. 38 (2): 388–94. doi:10.1161/01.STR.0000254462.75851.22. PMID17204689.
^Green AR, Ashwood T (Apr 2005). "Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers". Current Drug Targets. CNS and Neurological Disorders. 4 (2): 109–18. doi:10.2174/1568007053544156. PMID15857295.
^ abLemmo W (Sep 2014). "Potential interactions of prescription and over-the-counter medications having antioxidant capabilities with radiation and chemotherapy". International Journal of Cancer. Journal International Du Cancer. 137 (11): 2525–33. doi:10.1002/ijc.29208. PMID25220632.
^Mastaloudis A, Traber MG, Carstensen K, Widrick JJ (Jan 2006). "Antioxidants did not prevent muscle damage in response to an ultramarathon run". Medicine and Science in Sports and Exercise. 38 (1): 72–80. doi:10.1249/01.mss.0000188579.36272.f6. PMID16394956.
^Close GL, Ashton T, Cable T, Doran D, Holloway C, McArdle F, MacLaren DP (May 2006). "Ascorbic acid supplementation does not attenuate post-exercise muscle soreness following muscle-damaging exercise but may delay the recovery process". The British Journal of Nutrition. 95 (5): 976–81. doi:10.1079/BJN20061732. PMID16611389.
^Gibson RS, Perlas L, Hotz C (May 2006). "Improving the bioavailability of nutrients in plant foods at the household level". The Proceedings of the Nutrition Society. 65 (2): 160–8. doi:10.1079/PNS2006489. PMID16672077.
^ abMosha TC, Gaga HE, Pace RD, Laswai HS, Mtebe K (Jun 1995). "Effect of blanching on the content of antinutritional factors in selected vegetables". Plant Foods for Human Nutrition. 47 (4): 361–7. doi:10.1007/BF01088275. PMID8577655.
^Hornig D, Vuilleumier JP, Hartmann D (1980). "Absorption of large, single, oral intakes of ascorbic acid". International Journal for Vitamin and Nutrition Research. 50 (3): 309–14. PMID7429760.
^Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S, Cherniack MG, Brodkin CA, Hammar S (Nov 1996). "Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial". Journal of the National Cancer Institute. 88 (21): 1550–9. doi:10.1093/jnci/88.21.1550. PMID8901853.
^ abBjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (14 March 2012). "Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases". The Cochrane Database of Systematic Reviews. 3 (3): CD007176. doi:10.1002/14651858.CD007176.pub2. PMID22419320.
^Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (Jan 2005). "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality". Annals of Internal Medicine. 142 (1): 37–46. doi:10.7326/0003-4819-142-1-200501040-00110. PMID15537682.
^ abBjelakovic G, Nagorni A, Nikolova D, Simonetti RG, Bjelakovic M, Gluud C (Jul 2006). "Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma". Alimentary Pharmacology & Therapeutics. 24 (2): 281–91. doi:10.1111/j.1365-2036.2006.02970.x. PMID16842454.
^Cortés-Jofré M, Rueda JR, Corsini-Muñoz G, Fonseca-Cortés C, Caraballoso M, Bonfill Cosp X (17 October 2012). "Drugs for preventing lung cancer in healthy people". The Cochrane Database of Systematic Reviews. 10: CD002141. doi:10.1002/14651858.CD002141.pub2. PMID23076895.
^Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB (Jun 2008). "Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?". Journal of the National Cancer Institute. 100 (11): 773–83. doi:10.1093/jnci/djn148. PMID18505970.
^Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C (Sep 2008). "Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials". International Journal of Cancer. Journal International Du Cancer. 123 (6): 1227–39. doi:10.1002/ijc.23754. PMID18623084.
^Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C (Aug 2007). "Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials". Cancer Treatment Reviews. 33 (5): 407–18. doi:10.1016/j.ctrv.2007.01.005. PMID17367938.
^ abValko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007). "Free radicals and antioxidants in normal physiological functions and human disease". The International Journal of Biochemistry & Cell Biology. 39 (1): 44–84. doi:10.1016/j.biocel.2006.07.001. PMID16978905.
^ abcdEvelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi EA (Apr 2001). "Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols". Archives of Biochemistry and Biophysics. 388 (2): 261–6. doi:10.1006/abbi.2001.2292. PMID11368163.
^Teichert J, Preiss R (Nov 1992). "HPLC-methods for determination of lipoic acid and its reduced form in human plasma". International Journal of Clinical Pharmacology, Therapy, and Toxicology. 30 (11): 511–2. PMID1490813.
^Akiba S, Matsugo S, Packer L, Konishi T (May 1998). "Assay of protein-bound lipoic acid in tissues by a new enzymatic method". Analytical Biochemistry. 258 (2): 299–304. doi:10.1006/abio.1998.2615. PMID9570844.
^Stahl W, Schwarz W, Sundquist AR, Sies H (Apr 1992). "cis-trans isomers of lycopene and beta-carotene in human serum and tissues". Archives of Biochemistry and Biophysics. 294 (1): 173–7. doi:10.1016/0003-9861(92)90153-N. PMID1550343.
^Zita C, Overvad K, Mortensen SA, Sindberg CD, Moesgaard S, Hunter DA (2003). "Serum coenzyme Q10 concentrations in healthy men supplemented with 30 mg or 100 mg coenzyme Q10 for two months in a randomised controlled study". BioFactors. 18 (1–4): 185–93. doi:10.1002/biof.5520180221. PMID14695934.
^ abEnomoto A, Endou H (Sep 2005). "Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease". Clinical and Experimental Nephrology. 9 (3): 195–205. doi:10.1007/s10157-005-0368-5. PMID16189627.
^Wu XW, Muzny DM, Lee CC, Caskey CT (Jan 1992). "Two independent mutational events in the loss of urate oxidase during hominoid evolution". Journal of Molecular Evolution. 34 (1): 78–84. doi:10.1007/BF00163854. PMID1556746.
^ abWatanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, Mazzali M, Johnson RJ (Sep 2002). "Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity". Hypertension. 40 (3): 355–60. doi:10.1161/01.HYP.0000028589.66335.AA. PMID12215479.
^Campion EW, Glynn RJ, DeLabry LO (Mar 1987). "Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study". The American Journal of Medicine. 82 (3): 421–6. doi:10.1016/0002-9343(87)90441-4. PMID3826098.
^Nazarewicz RR, Ziolkowski W, Vaccaro PS, Ghafourifar P (Dec 2007). "Effect of short-term ketogenic diet on redox status of human blood". Rejuvenation Research. 10 (4): 435–40. doi:10.1089/rej.2007.0540. PMID17663642.
^Shigeoka S, Ishikawa T, Tamoi M, Miyagawa Y, Takeda T, Yabuta Y, Yoshimura K (May 2002). "Regulation and function of ascorbate peroxidase isoenzymes". Journal of Experimental Botany. 53 (372): 1305–19. doi:10.1093/jexbot/53.372.1305. PMID11997377.
^Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (Jan 2007). "One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?". Journal of Pineal Research. 42 (1): 28–42. doi:10.1111/j.1600-079X.2006.00407.x. PMID17198536.
^Reiter RJ, Paredes SD, Manchester LC, Tan DX (2009). "Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin". Critical Reviews in Biochemistry and Molecular Biology. 44 (4): 175–200. doi:10.1080/10409230903044914. PMID19635037.
^Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR (2000). "Significance of melatonin in antioxidative defense system: reactions and products". Biological Signals and Receptors. 9 (3–4): 137–59. doi:10.1159/000014635. PMID10899700.
^ abHerrera E, Barbas C (Mar 2001). "Vitamin E: action, metabolism and perspectives". Journal of Physiology and Biochemistry. 57 (2): 43–56. doi:10.1007/BF03179812. PMID11579997.
^Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (Sep 2008). "Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death". Cell Metabolism. 8 (3): 237–48. doi:10.1016/j.cmet.2008.07.005. PMID18762024.
^Brigelius-Flohé R, Davies KJ (Jul 2007). "Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food? Comments on the two accompanying papers: "Molecular mechanism of alpha-tocopherol action" by A. Azzi and "Vitamin E, antioxidant and nothing more" by M. Traber and J. Atkinson". Free Radical Biology & Medicine. 43 (1): 2–3. doi:10.1016/j.freeradbiomed.2007.05.016. PMID17561087.
^Duarte TL, Lunec J (Jul 2005). "Review: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C". Free Radical Research. 39 (7): 671–86. doi:10.1080/10715760500104025. PMID16036346.
^Halliwell B (Aug 2008). "Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?". Archives of Biochemistry and Biophysics. 476 (2): 107–112. doi:10.1016/j.abb.2008.01.028. PMID18284912.
^ abcdRistow M, Zarse K (Jun 2010). "How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)". Experimental Gerontology. 45 (6): 410–418. doi:10.1016/j.exger.2010.03.014. PMID20350594.
^Tapia PC (2006). "Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality". Medical Hypotheses. 66 (4): 832–43. doi:10.1016/j.mehy.2005.09.009. PMID16242247.
^Zelko IN, Mariani TJ, Folz RJ (Aug 2002). "Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression". Free Radical Biology & Medicine. 33 (3): 337–49. doi:10.1016/S0891-5849(02)00905-X. PMID12126755.
^ abBannister JV, Bannister WH, Rotilio G (1987). "Aspects of the structure, function, and applications of superoxide dismutase". CRC Critical Reviews in Biochemistry. 22 (2): 111–80. doi:10.3109/10409238709083738. PMID3315461.
^Zámocký M, Koller F (1999). "Understanding the structure and function of catalases: clues from molecular evolution and in vitro mutagenesis". Progress in Biophysics and Molecular Biology. 72 (1): 19–66. doi:10.1016/S0079-6107(98)00058-3. PMID10446501.
^del Río LA, Sandalio LM, Palma JM, Bueno P, Corpas FJ (Nov 1992). "Metabolism of oxygen radicals in peroxisomes and cellular implications". Free Radical Biology & Medicine. 13 (5): 557–80. doi:10.1016/0891-5849(92)90150-F. PMID1334030.
^Hiner AN, Raven EL, Thorneley RN, García-Cánovas F, Rodríguez-López JN (Jul 2002). "Mechanisms of compound I formation in heme peroxidases". Journal of Inorganic Biochemistry. 91 (1): 27–34. doi:10.1016/S0162-0134(02)00390-2. PMID12121759.
^Rhee SG, Chae HZ, Kim K (Jun 2005). "Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling". Free Radical Biology & Medicine. 38 (12): 1543–52. doi:10.1016/j.freeradbiomed.2005.02.026. PMID15917183.
^Claiborne A, Yeh JI, Mallett TC, Luba J, Crane EJ, Charrier V, Parsonage D (Nov 1999). "Protein-sulfenic acids: diverse roles for an unlikely player in enzyme catalysis and redox regulation". Biochemistry. 38 (47): 15407–16. doi:10.1021/bi992025k. PMID10569923.
^Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH, Van Etten RA (Jul 2003). "Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression". Nature. 424 (6948): 561–5. Bibcode:2003Natur.424..561N. doi:10.1038/nature01819. PMID12891360.
^Dietz KJ, Jacob S, Oelze ML, Laxa M, Tognetti V, de Miranda SM, Baier M, Finkemeier I (2006). "The function of peroxiredoxins in plant organelle redox metabolism". Journal of Experimental Botany. 57 (8): 1697–709. doi:10.1093/jxb/erj160. PMID16606633.
^Ho YS, Magnenat JL, Bronson RT, Cao J, Gargano M, Sugawara M, Funk CD (Jun 1997). "Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia". The Journal of Biological Chemistry. 272 (26): 16644–51. doi:10.1074/jbc.272.26.16644. PMID9195979.
^de Haan JB, Bladier C, Griffiths P, Kelner M, O'Shea RD, Cheung NS, Bronson RT, Silvestro MJ, Wild S, Zheng SS, Beart PM, Hertzog PJ, Kola I (Aug 1998). "Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide". The Journal of Biological Chemistry. 273 (35): 22528–36. doi:10.1074/jbc.273.35.22528. PMID9712879.
^Sharma R, Yang Y, Sharma A, Awasthi S, Awasthi YC (Apr 2004). "Antioxidant role of glutathione S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis". Antioxidants & Redox Signaling. 6 (2): 289–300. doi:10.1089/152308604322899350. PMID15025930.
^Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA (Jul 2006). "Involvement of oxidative stress in Alzheimer disease". Journal of Neuropathology and Experimental Neurology. 65 (7): 631–41. doi:10.1097/01.jnen.0000228136.58062.bf. PMID16825950.
^Del Carlo M, Sacchetti G, Di Mattia C, Compagnone D, Mastrocola D, Liberatore L, Cichelli A (Jun 2004). "Contribution of the phenolic fraction to the antioxidant activity and oxidative stability of olive oil". Journal of Agricultural and Food Chemistry. 52 (13): 4072–9. doi:10.1021/jf049806z. PMID15212450.
^Boozer CE, Hammond GS, Hamilton CE, Sen JN (1955). "Air Oxidation of Hydrocarbons.1II. The Stoichiometry and Fate of Inhibitors in Benzene and Chlorobenzene". Journal of the American Chemical Society. 77 (12): 3233–7. Bibcode:1955JAChS..77.1678G. doi:10.1021/ja01617a026.
^Witschi A, Reddy S, Stofer B, Lauterburg BH (1992). "The systemic availability of oral glutathione". European Journal of Clinical Pharmacology. 43 (6): 667–9. doi:10.1007/BF02284971. PMID1362956.
^Flagg EW, Coates RJ, Eley JW, Jones DP, Gunter EW, Byers TE, Block GS, Greenberg RS (1994). "Dietary glutathione intake in humans and the relationship between intake and plasma total glutathione level". Nutrition and Cancer. 21 (1): 33–46. doi:10.1080/01635589409514302. PMID8183721.
^Dodd S, Dean O, Copolov DL, Malhi GS, Berk M (Dec 2008). "N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility". Expert Opinion on Biological Therapy. 8 (12): 1955–62. doi:10.1517/14728220802517901. PMID18990082.
^van de Poll MC, Dejong CH, Soeters PB (Jun 2006). "Adequate range for sulfur-containing amino acids and biomarkers for their excess: lessons from enteral and parenteral nutrition". The Journal of Nutrition. 136 (6 Suppl): 1694S–1700S. PMID16702341.
^Ou B, Hampsch-Woodill M, Prior RL (Oct 2001). "Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe". Journal of Agricultural and Food Chemistry. 49 (10): 4619–26. doi:10.1021/jf010586o. PMID11599998.
^Prior RL, Wu X, Schaich K (May 2005). "Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements". Journal of Agricultural and Food Chemistry. 53 (10): 4290–302. doi:10.1021/jf0502698. PMID15884874.