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.
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, vitamin A, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Insufficient levels of antioxidants, or inhibition of the antioxidant enzymes, cause oxidative stress and may damage or kill cells. Oxidative stress is damage to cell structure and cell function by overly reactive oxygen-containing molecules and chronic excessive inflammation. Oxidative stress seems to play a significant role in many human diseases, including cancers. The use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. For these reasons, oxidative stress can be considered to be both the cause and the consequence of some diseases.
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 detected no benefit and even suggested that excess supplementation with certain putative antioxidants may be harmful. Antioxidants also have many industrial uses, such as preservatives in food and cosmetics and to prevent the degradation of rubber and gasoline.
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.
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. 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. Studies of UA's antioxidant mechanism support this proposal.
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." In sum, while the mechanism of UA as an antioxidant is well-supported, the claim that its levels affect MS risk is still controversial, and requires more research.
Likewise, UA 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 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. 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.
Potential of antioxidant supplements to damage health
Some antioxidant supplements may promote disease and increase mortality in humans. Hypothetically, free radicals induce an endogenous response which protects against exogenous radicals (and possibly other toxic compounds). 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. 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.
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.
A low calorie diet extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress. While there is some evidence to support the role of oxidative stress in aging in model organisms such as Drosophila melanogaster and Caenorhabditis elegans, the evidence in mammals is less clear. Indeed, a 2009 review of experiments in mice concluded that almost all manipulations of antioxidant systems had no effect on aging. 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. 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, and it may be these other effects that are the real reason these compounds are important in human nutrition.
Structure of resveratrol under study for its potential as a dietary antioxidant
People who eat fruits and vegetables have a lower risk of heart disease and some neurological diseases, and there is evidence that some types of vegetables, and fruits in general, may lower risk against some cancers. 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. 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. 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.
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. 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. Further studies have also been negative. 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. 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.
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. 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.
Although some levels of antioxidant vitamins and minerals in the diet are required for good health, there is considerable doubt as to whether antioxidant supplements are beneficial or harmful; and if they are actually beneficial, which antioxidant(s) are needed and in what amounts. 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. 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.
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. The suggestion that increased life expectancy comes from increased oxidative stress conflicts with results seen in the yeast Saccharomyces cerevisiae, and the situation in mammals is even less clear. Nevertheless, antioxidant supplements do not appear to increase life expectancy in humans.
During exercise, oxygen consumption can increase by a factor of more than 10. 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. Antioxidant supplements may also prevent any of the health gains that normally come from exercise, such as increased insulin sensitivity.
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. 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.
No benefits for physical performance to athletes are seen with vitamin E supplementation. 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. 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. Other studies found no such effects, and some research suggests that supplementation with amounts as high as 1000 mg inhibits recovery.
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.
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 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. 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. 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. 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 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.
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) used to be the industry standard for antioxidant strength of whole foods, juices and food additives. However, the United States Department of Agriculture (USDA) withdrew these ratings in 2012 as biologically invalid, stating that no physiological proof in vivo existed to support the free-radical theory. Consequently, the ORAC method, derived only in in vitro experiments, is no longer considered relevant to human diets or biology.
Antioxidants are found in vegetables, fruits, grain cereals, eggs, meat, legumes and nuts. Some, such as lycopene and ascorbic acid, can be destroyed by long-term storage or prolonged cooking. Other antioxidant compounds are more stable, such as the polyphenolic antioxidants in foods such as whole-wheat cereals and tea. 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 antioxidants than fresh and uncooked foods, as preparation exposes food to oxygen.
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. 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. 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. 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.
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. 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.
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.
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 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).
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.
^ abValko, M; Leibfritz, D; Moncol, J; Cronin, M; Mazur, M; Telser, J (2007). "Free radicals and antioxidants in normal physiological functions and human disease". The International Journal of Biochemistry & Cell Biology39 (1): 44–84. doi:10.1016/j.biocel.2006.07.001. PMID16978905.
^Nakabeppu, Yusaku; Sakumi, Kunihiko; Sakamoto, Katsumi; Tsuchimoto, Daisuke; Tsuzuki, Teruhisa; Nakatsu, Yoshimichi (2006). "Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids". Biological Chemistry387 (4): 373–9. doi:10.1515/BC.2006.050. PMID16606334.
^Valko, Marian; Izakovic, Mario; Mazur, Milan; Rhodes, Christopher J.; Telser, Joshua (2004). "Role of oxygen radicals in DNA damage and cancer incidence". Molecular and Cellular Biochemistry266 (1–2): 37–56. doi:10.1023/B:MCBI.0000049134.69131.89. PMID15646026.
^Finkel, Toren; Holbrook, Nikki J. (2000). "Oxidants, oxidative stress and the biology of ageing". Nature408 (6809): 239–47. doi:10.1038/35041687. PMID11089981.
^Hirst, Judy; King, Martin S.; Pryde, Kenneth R. (2008). "The production of reactive oxygen species by complex I". Biochemical Society Transactions36 (5): 976–80. doi:10.1042/BST0360976.
^Seaver, L. C.; Imlay, JA (2004). "Are Respiratory Enzymes the Primary Sources of Intracellular Hydrogen Peroxide?". Journal of Biological Chemistry279 (47): 48742–50. doi:10.1074/jbc.M408754200. PMID15361522.
^ abcdEvelson, P; Travacio, M; Repetto, M; Escobar, J; Llesuy, S; Lissi, EA (2001). "Evaluation of Total Reactive Antioxidant Potential (TRAP) of Tissue Homogenates and Their Cytosols". Archives of Biochemistry and Biophysics388 (2): 261–6. doi:10.1006/abbi.2001.2292. PMID11368163.
^Morrison, John A.; Jacobsen, Donald W.; Sprecher, Dennis L.; Robinson, Killian; Khoury, Philip; Daniels, Stephen R. (1999). "Serum glutathione in adolescent males predicts parental coronary heart disease". Circulation100 (22): 2244–7. doi:10.1161/01.CIR.100.22.2244. PMID10577998.
^Teichert, J; Preiss, R (1992). "HPLC-methods for determination of lipoic acid and its reduced form in human plasma". International journal of clinical pharmacology, therapy, and toxicology30 (11): 511–2. PMID1490813.
^Akiba, S; Matsugo, S; Packer, L; Konishi, T (1998). "Assay of Protein-Bound Lipoic Acid in Tissues by a New Enzymatic Method". Analytical Biochemistry258 (2): 299–304. doi:10.1006/abio.1998.2615. PMID9570844.
^Stahl, W; Schwarz, W; Sundquist, AR; Sies, H (1992). "cis-trans isomers of lycopene and ?-carotene in human serum and tissues". Archives of Biochemistry and Biophysics294 (1): 173–7. doi:10.1016/0003-9861(92)90153-N. PMID1550343.
^Zita, ČEstmír; Overvad, Kim; Mortensen, Svend Aage; Sindberg, Christian Dan; Moesgaard, Sven; Hunter, Douglas A. (2003). "Serum coenzyme Q10concentrations in healthy men supplemented with 30 mg or 100 mg coenzyme Q10 for two months in a randomised controlled study". BioFactors18 (1–4): 185–93. doi:10.1002/biof.5520180221. PMID14695934.
^ abEnomoto, Atsushi; Endou, Hitoshi (2005). "Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease". Clinical and Experimental Nephrology9 (3): 195–205. doi:10.1007/s10157-005-0368-5. PMID16189627.
^Wu, Xiangwei; Muzny, Donna M.; Lee, Cheng; Caskey, C. (1992). "Two independent mutational events in the loss of urate oxidase during hominoid evolution". Journal of Molecular Evolution34 (1): 78–84. doi:10.1007/BF00163854. PMID1556746.
^ abBaillie, J. K.; Bates, M. G. D.; Thompson, A. A. R.; Waring, W. S.; Partridge, R. W.; Schnopp, M. F.; Simpson, A.; Gulliver-Sloan, F.; Maxwell, S. R. J.; Webb, DJ (2007). "Endogenous Urate Production Augments Plasma Antioxidant Capacity in Healthy Lowland Subjects Exposed to High Altitude". Chest131 (5): 1473–8. doi:10.1378/chest.06-2235. PMID17494796.
^Campion, E; Glynn, RJ; Delabry, LO (1987). "Asymptomatic hyperuricemia. Risks and consequences in the normative aging study*1". The American Journal of Medicine82 (3): 421–6. doi:10.1016/0002-9343(87)90441-4. PMID3826098.
^Nazarewicz, Rafal R.; Ziolkowski, Wieslaw; Vaccaro, Patrick S.; Ghafourifar, Pedram (2007). "Effect of Short-Term Ketogenic Diet on Redox Status of Human Blood". Rejuvenation Research10 (4): 435–40. doi:10.1089/rej.2007.0540. PMID17663642.
^Shigeoka, S.; Ishikawa, T; Tamoi, M; Miyagawa, Y; Takeda, T; Yabuta, Y; Yoshimura, K (2002). "Regulation and function of ascorbate peroxidase isoenzymes". Journal of Experimental Botany53 (372): 1305–19. doi:10.1093/jexbot/53.372.1305. PMID11997377.
^Smirnoff, Nicholas; Wheeler, Glen L. (2000). "Ascorbic Acid in Plants: Biosynthesis and Function". Critical Reviews in Biochemistry and Molecular Biology35 (4): 291–314. doi:10.1080/10409230008984166. PMID11005203.
^Seiler, Alexander; Schneider, Manuela; Förster, Heidi; Roth, Stephan; Wirth, Eva K.; Culmsee, Carsten; Plesnila, Nikolaus; Kremmer, Elisabeth; Rådmark, Olof; Wurst, Wolfgang; Bornkamm, Georg W.; Schweizer, Ulrich; Conrad, Marcus (2008). "Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death". Cell Metabolism8 (3): 237–48. doi:10.1016/j.cmet.2008.07.005. PMID18762024.
^Brigelius-Flohé, Regina; Davies, Kelvin J.A. (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 α-tocopherol action' by A. Azzi and 'Vitamin E, antioxidant and nothing more' by M. Traber and J. Atkinson". Free Radical Biology and Medicine43 (1): 2–3. doi:10.1016/j.freeradbiomed.2007.05.016. PMID17561087.
^Duarte TL, Lunec J (2005). "Review: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C". Free Radic. Res.39 (7): 671–86. doi:10.1080/10715760500104025. PMID16036346.
^Halliwell, B. (2008). "Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?". Archives of Biochemistry and Biophysics476 (2): 107–112. doi:10.1016/j.abb.2008.01.028. PMID18284912.
^ abcRistow, M. .; Zarse, K. . (2010). "How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis)". Experimental Gerontology45 (6): 410–418. doi:10.1016/j.exger.2010.03.014. PMID20350594.edit
^Tapia, P (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 Hypotheses66 (4): 832–43. doi:10.1016/j.mehy.2005.09.009. PMID16242247.
^Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007). "Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress". Cell Metab.6 (4): 280–93. doi:10.1016/j.cmet.2007.08.011. PMID17908557.
^Zelko I, Mariani T, Folz R (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 Radic Biol Med33 (3): 337–49. doi:10.1016/S0891-5849(02)00905-X. PMID12126755.
^ abBannister J, Bannister W, Rotilio G (1987). "Aspects of the structure, function, and applications of superoxide dismutase". CRC Crit Rev Biochem22 (2): 111–80. doi:10.3109/10409238709083738. PMID3315461.
^Melov S, Schneider J, Day B, Hinerfeld D, Coskun P, Mirra S, Crapo J, Wallace D (1998). "A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase". Nat Genet18 (2): 159–63. doi:10.1038/ng0298-159. PMID9462746.
^Reaume A, Elliott J, Hoffman E, Kowall N, Ferrante R, Siwek D, Wilcox H, Flood D, Beal M, Brown R, Scott R, Snider W (1996). "Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury". Nat Genet13 (1): 43–7. doi:10.1038/ng0596-43. PMID8673102.
^Zámocký M, Koller F (1999). "Understanding the structure and function of catalases: clues from molecular evolution and in vitro mutagenesis". Prog Biophys Mol Biol72 (1): 19–66. doi:10.1016/S0079-6107(98)00058-3. PMID10446501.
^Claiborne A, Yeh J, Mallett T, Luba J, Crane E, Charrier V, Parsonage D (1999). "Protein-sulfenic acids: diverse roles for an unlikely player in enzyme catalysis and redox regulation". Biochemistry38 (47): 15407–16. doi:10.1021/bi992025k. PMID10569923.
^Neumann C, Krause D, Carman C, Das S, Dubey D, Abraham J, Bronson R, Fujiwara Y, Orkin S, Van Etten R (2003). "Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression". Nature424 (6948): 561–5. doi:10.1038/nature01819. PMID12891360.
^Dietz K, Jacob S, Oelze M, Laxa M, Tognetti V, de Miranda S, Baier M, Finkemeier I (2006). "The function of peroxiredoxins in plant organelle redox metabolism". J Exp Bot57 (8): 1697–709. doi:10.1093/jxb/erj160. PMID16606633.
^Ho Y, Magnenat J, Bronson R, Cao J, Gargano M, Sugawara M, Funk C (1997). "Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia". J Biol Chem272 (26): 16644–51. doi:10.1074/jbc.272.26.16644. PMID9195979.
^de Haan J, Bladier C, Griffiths P, Kelner M, O'Shea R, Cheung N, Bronson R, Silvestro M, Wild S, Zheng S, Beart P, Hertzog P, Kola I (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". J Biol Chem273 (35): 22528–36. doi:10.1074/jbc.273.35.22528. PMID9712879.
^Sharma R, Yang Y, Sharma A, Awasthi S, Awasthi Y (2004). "Antioxidant role of glutathione S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis". Antioxid Redox Signal6 (2): 289–300. doi:10.1089/152308604322899350. PMID15025930.
^Lees K, Davalos A, Davis S, Diener H, Grotta J, Lyden P, Shuaib A, Ashwood T, Hardemark H, Wasiewski W, Emeribe U, Zivin J (2006). "Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial". Stroke37 (12): 2970–8. doi:10.1161/01.STR.0000249410.91473.44. PMID17068304.
^Lees K, Zivin J, Ashwood T, Davalos A, Davis S, Diener H, Grotta J, Lyden P, Shuaib A, Hårdemark H, Wasiewski W (2006). "NXY-059 for acute ischemic stroke". N Engl J Med354 (6): 588–600. doi:10.1056/NEJMoa052980. PMID16467546.
^Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H (1998). "Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group". Stroke29 (1): 12–7. doi:10.1161/01.STR.29.1.12. PMID9445321.
^Di Matteo V, Esposito E (2003). "Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis". Curr Drug Targets CNS Neurol Disord2 (2): 95–107. doi:10.2174/1568007033482959. PMID12769802.
^ abcdStanner SA, Hughes J, Kelly CN, Buttriss J (2004). "A review of the epidemiological evidence for the 'antioxidant hypothesis'". Public Health Nutr7 (3): 407–22. doi:10.1079/PHN2003543. PMID15153272.
^Cherubini A, Vigna G, Zuliani G, Ruggiero C, Senin U, Fellin R (2005). "Role of antioxidants in atherosclerosis: epidemiological and clinical update". Curr Pharm Des11 (16): 2017–32. doi:10.2174/1381612054065783. PMID15974956.
^Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC (1993). "Vitamin E consumption and the risk of coronary heart disease in men". N Engl J Med328 (20): 1450–6. doi:10.1056/NEJM199305203282004. PMID8479464.
^Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ (2003). "Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials". Lancet361 (9374): 2017–23. doi:10.1016/S0140-6736(03)13637-9. PMID12814711.
^Lee IM, Cook NR, Gaziano JM (2005). "Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial". JAMA294 (1): 56–65. doi:10.1001/jama.294.1.56. PMID15998891.
^Bleys J, Miller E, Pastor-Barriuso R, Appel L, Guallar E (2006). "Vitamin-mineral supplementation and the progression of atherosclerosis: a meta-analysis of randomized controlled trials". Am. J. Clin. Nutr.84 (4): 880–7; quiz 954–5. PMID17023716.
^ abHercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, Roussel AM, Favier A, Briancon S (2004). "The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals". Arch Intern Med164 (21): 2335–42. doi:10.1001/archinte.164.21.2335. PMID15557412.
^Woodside J, McCall D, McGartland C, Young I (2005). "Micronutrients: dietary intake v. supplement use". Proc Nutr Soc64 (4): 543–53. doi:10.1079/PNS2005464. PMID16313697.
^Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007). "Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress". Cell Metab.6 (4): 280–93. doi:10.1016/j.cmet.2007.08.011. PMID17908557.
^Barros MH, Bandy B, Tahara EB, Kowaltowski AJ (2004). "Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae". J. Biol. Chem.279 (48): 49883–8. doi:10.1074/jbc.M408918200. PMID15383542.
^Green GA (2008). "Review: antioxidant supplements do not reduce all-cause mortality in primary or secondary prevention". Evid Based Med13 (6): 177. doi:10.1136/ebm.13.6.177. PMID19043035.
^Gibson R, Perlas L, Hotz C (2006). "Improving the bioavailability of nutrients in plant foods at the household level". Proc Nutr Soc65 (2): 160–8. doi:10.1079/PNS2006489. PMID16672077.
^ abMosha T, Gaga H, Pace R, Laswai H, Mtebe K (1995). "Effect of blanching on the content of antinutritional factors in selected vegetables". Plant Foods Hum Nutr47 (4): 361–7. doi:10.1007/BF01088275. PMID8577655.
^Hornig D, Vuilleumier J, Hartmann D (1980). "Absorption of large, single, oral intakes of ascorbic acid". Int J Vitam Nutr Res50 (3): 309–14. PMID7429760.
^Omenn G, Goodman G, Thornquist M, Balmes J, Cullen M, Glass A, Keogh J, Meyskens F, Valanis B, Williams J, Barnhart S, Cherniack M, Brodkin C, Hammar S (1996). "Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial". J Natl Cancer Inst88 (21): 1550–9. doi:10.1093/jnci/88.21.1550. PMID8901853.
^Bjelakovic, G; D Nikolova, L L Gluud, R G Simonetti, C Gluud (2008). "Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases". In Bjelakovic, Goran. Cochrane database of systematic reviews (Online) (2): CD007176. doi:10.1002/14651858.CD007176. ISSN1469-493X. PMID18425980.Cite uses deprecated parameters (help)
^Bjelakovic G, Nagorni A, Nikolova D, Simonetti R, Bjelakovic M, Gluud C (2006). "Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma". Aliment Pharmacol Ther24 (2): 281–91. doi:10.1111/j.1365-2036.2006.02970.x. PMID16842454.
^Caraballoso M, Sacristan M, Serra C, Bonfill X (2003). "Drugs for preventing lung cancer in healthy people". In Caraballoso, Magali. Cochrane Database Syst Rev (2): CD002141. doi:10.1002/14651858.CD002141. PMID12804424.
^Bjelakovic G, Nagorni A, Nikolova D, Simonetti R, Bjelakovic M, Gluud C (2006). "Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma". Aliment. Pharmacol. Ther.24 (2): 281–91. doi:10.1111/j.1365-2036.2006.02970.x. PMID16842454.
^Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB (2008). "Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?". J. Natl. Cancer Inst.100 (11): 773–83. doi:10.1093/jnci/djn148. PMID18505970.
^Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C (2008). "Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials". Int. J. Cancer123 (6): 1227–39. doi:10.1002/ijc.23754. PMID18623084.
^Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C (2007). "Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials". Cancer Treat. Rev.33 (5): 407–18. doi:10.1016/j.ctrv.2007.01.005. PMID17367938.
^Ou B, Hampsch-Woodill M, Prior R (2001). "Development and validation of an improved oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe". Journal of Agricultural and Food Chemistry49 (10): 4619–26. doi:10.1021/jf010586o. PMID11599998.
^Prior R, Wu X, Schaich K (2005). "Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements". Journal of Agricultural and Food Chemistry53 (10): 4290–302. doi:10.1021/jf0502698. PMID15884874.
^Maiani G, Periago Castón MJ, Catasta G (2008). "Carotenoids: Actual knowledge on food sources, intakes, stability and bioavailability and their protective role in humans". Mol Nutr Food Res53: S194–218. doi:10.1002/mnfr.200800053. PMID19035552.
^Goodrow EF, Wilson TA, Houde SC (2006). "Consumption of one egg per day increases serum lutein and zeaxanthin concentrations in older adults without altering serum lipid and lipoprotein cholesterol concentrations". J. Nutr.136 (10): 2519–24. PMID16988120.
^Witschi A, Reddy S, Stofer B, Lauterburg B (1992). "The systemic availability of oral glutathione". Eur J Clin Pharmacol43 (6): 667–9. doi:10.1007/BF02284971. PMID1362956.
^Flagg EW, Coates RJ, Eley JW (1994). "Dietary glutathione intake in humans and the relationship between intake and plasma total glutathione level". Nutr Cancer21 (1): 33–46. doi:10.1080/01635589409514302. PMID8183721.
^ abDodd S, Dean O, Copolov DL, Malhi GS, Berk M (2008). "N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility". Expert Opin Biol Ther8 (12): 1955–62. doi:10.1517/14728220802517901. PMID18990082.
^van de Poll MC, Dejong CH, Soeters PB (2006). "Adequate range for sulfur-containing amino acids and biomarkers for their excess: lessons from enteral and parenteral nutrition". J. Nutr.136 (6 Suppl): 1694S–1700S. PMID16702341.
^Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (2004). "Glutathione metabolism and its implications for health". J. Nutr.134 (3): 489–92. PMID14988435.
^Pan MH, Ho CT (2008). "Chemopreventive effects of natural dietary compounds on cancer development". Chem Soc Rev37 (11): 2558–74. doi:10.1039/b801558a. PMID18949126.
^Robards K, Kerr A, Patsalides E (1988). "Rancidity and its measurement in edible oils and snack foods. A review". Analyst113 (2): 213–24. doi:10.1039/an9881300213. PMID3288002.
^Del Carlo M, Sacchetti G, Di Mattia C, Compagnone D, Mastrocola D, Liberatore L, Cichelli A (2004). "Contribution of the phenolic fraction to the antioxidant activity and oxidative stability of olive oil". Journal of Agricultural and Food Chemistry52 (13): 4072–9. doi:10.1021/jf049806z. PMID15212450.
^Boozer, Charles E.; Hammond, George S.; Hamilton, Chester E.; Sen, Jyotirindra N. (1955). "Air Oxidation of Hydrocarbons.1II. The Stoichiometry and Fate of Inhibitors in Benzene and Chlorobenzene". Journal of the American Chemical Society77 (12): 3233–7. doi:10.1021/ja01617a026.