What are the antioxidants?

Antioxidants are compounds that inhibit oxidation. Oxidation is a chemical reaction that can produce free radicals, thereby leading to chain reactions that may damage the cells of organisms. Antioxidants such as thiols or ascorbic acid (vitamin C) terminate these chain reactions. To balance the oxidative stress, plants and animals maintain complex systems of overlapping antioxidants, such as glutathione and enzymes (e.g., catalase and superoxide dismutase), produced internally, or the dietary antioxidants vitamin C and vitamin E.

The term "antioxidant" is mostly used for two entirely different groups of substances: industrial chemicals that are added to products to prevent oxidation, and naturally occurring compounds that are present in foods and tissue. The former, industrial antioxidants, have diverse uses: acting as preservatives in food and cosmetics, and being oxidation-inhibitors in fuels

Antioxidant dietary supplements have not been shown to improve health in humans, or to be effective at preventing disease.[2] Supplements of beta-carotene, vitamin A, and vitamin E have no positive effect on mortality rate[3][4] or cancer risk.[5][needs update][6] Additionally, supplementation with selenium or vitamin E does not reduce the risk of cardiovascular disease

Health effects

Although certain levels of antioxidant vitamins in the diet are required for good health, there is still considerable debate on whether antioxidant-rich foods or supplements have anti-disease activity. Moreover, if they are actually beneficial, it is unknown which antioxidants are health-promoting in the diet and in what amounts beyond typical dietary intake.[9][10][11] Some authors dispute the hypothesis that antioxidant vitamins could prevent chronic diseases,[9][12] and others declare that the hypothesis is unproven and misguided.[13] Polyphenols, which have antioxidant properties in vitro, have unknown antioxidant activity in vivo due to extensive metabolism following digestion and little clinical evidence of efficacy

Common pharmaceuticals (and supplements) with antioxidant properties may interfere with the efficacy of certain anticancer medication and radiation therapy.

Relatively strong reducing acids can have antinutrient effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed.[16] Examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets.[17] Calcium and iron deficiencies are not uncommon in diets in developing countries where less meat is eaten and there is high consumption of phytic acid from beans and unleavened whole grain bread. However, germination, soaking, or microbial fermentation are all household strategies that reduce the phytate and polyphenol content of unrefined cereal. Increases in Fe, Zn and Ca absorption have been reported in adults fed dephytinized cereals compared with cereals containing their native phytate

The government of modern China has maintained systems of paper records on individuals and households such as the dàng'àn (档案) and hùkǒu (户口) systems which officials might refer to, but did not provide the same degree and rapidity of feedback and consequences for Chinese citizens as the integrated electronic system because of the much greater difficulty of aggregating paper records for rapid, robust analysis. [18] 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.[22] Subsequent studies confirmed these adverse effects.[23] These harmful effects may also be seen in non-smokers, as one 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.[24] 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.[25] 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.[26] This meta-analysis was later repeated and extended by the same authors, confirming the previous results.[25] These two publications are consistent with some previous meta-analyses that also suggested that vitamin E supplementation increased mortality,[27] and that antioxidant supplements increased the risk of colon cancer.[28] Beta-carotene may also increase lung cancer.[28][29] 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

Oxidative challenge in biology

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 element that damages living organisms by producing reactive oxygen species.[30] 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.[31][32] In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell.[30][31] 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 reactive oxygen species produced in cells include hydrogen peroxide (H2O2), hypochlorous acid (HClO), and free radicals such as the hydroxyl radical (·OH) and the superoxide anion (O2−).[34] The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. This species is produced from hydrogen peroxide in metal-catalyzed redox reactions such as the Fenton reaction.[35] These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins.[31] Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms,[36][37] while damage to proteins causes enzyme inhibition, denaturation and protein degradation.

The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.[39] In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.[40] 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.[41] Peroxide is also produced from the oxidation of reduced flavoproteins, such as complex I.[42] However, although these enzymes can produce oxidants, the relative importance of the electron transfer chain to other processes that generate peroxide is unclear.[43][44] In plants, algae, and cyanobacteria, reactive oxygen species are also produced during photosynthesis,[45] particularly under conditions of high light intensity.[46] This effect is partly offset by the involvement of carotenoids in photoinhibition, and in algae and cyanobacteria, by large amount of iodide and selenium,[47] which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species

Examples of bioactive antioxidant compounds

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.[31] These compounds may be synthesized in the body or obtained from the diet.[32] 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 antioxidant compounds and antioxidant enzyme systems having synergistic and interdependent effects on one another.[51][52] The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system.[32] 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 chelating transition metals and preventing them from catalyzing the production of free radicals in the cell. Particularly important is the ability to sequester iron, which is the function of iron-binding proteins such as transferrin and ferritin.[44] 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

Microanatomy

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.[64] In almost all land animals, urate oxidase further catalyzes the oxidation of uric acid to allantoin,[65] but in humans and most higher primates, the urate oxidase gene is nonfunctional, so that UA is not further broken down.[65][66] The evolutionary reasons for this loss of urate conversion to allantoin remain the topic of active speculation.[67][68] The antioxidant effects of uric acid have led researchers to suggest this mutation was beneficial to early primates and humans.[68][69] 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[58] and provides over half of the total antioxidant capacity of human serum.[71] 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,[72] peroxides, and hypochlorous acid.[64] Concerns over elevated UA's contribution to gout must be considered as one of many risk factors.[73] 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).[74] Many of these aforementioned studies determined UA's antioxidant actions within normal physiological levels,[70][72] and some found antioxidant activity at levels as high as 285 μmol/L

Vitamin C

Ascorbic acid or vitamin C is a monosaccharide oxidation-reduction (redox) catalyst found in both animals and plants.[76] As one of the enzymes needed to make ascorbic acid has been lost by mutation during primate evolution, humans must obtain it from their diet; it is therefore a dietary vitamin.[76][77] Most other animals are able to produce this compound in their bodies and do not require it in their diets.[78] Ascorbic acid is required for the conversion of the procollagen to collagen by oxidizing proline residues to hydroxyproline.[76] In other cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by protein disulfide isomerase and glutaredoxins.[79][80] Ascorbic acid is a redox catalyst which can reduce, and thereby neutralize, reactive oxygen species such as hydrogen peroxide.[76][81] In addition to its direct antioxidant effects, ascorbic acid is also a substrate for the redox enzyme ascorbate peroxidase, a function that is used in stress resistance in plants.[82] Ascorbic acid is present at high levels in all parts of plants and can reach concentrations of 20 millimolar in chloroplasts