A lot of BS on the tube and in the press about anti-oxidants. What the popular press and the CBC don't tell you is that anti-oxidants have a definite role to play in the body every day to prevent lipid peroxidation. Everyone in nutrition and medicine knows this. It has been established fora long time that E and A are not just fad vitamins but vital substances that when released from food in the small intestine, do very necessary things in the body.
The reason why some synthetic anti-oxidants APPEAR not to work may well be that the absorption and release rate within the system is not sufficient or sufficiently slow such that the complex processes of de-oxidation are properly attended to so to speak.
"The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.[14] In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.[15] 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 molecular oxygen and form the superoxide anion, instead of moving through the series of well-controlled reactions of the electron transport chain.[16]"
"Glutathione
Glutathione is a cysteine-containing peptide found in most forms of aerobic life.[36] It is not required in the diet and is instead synthesized in cells from its constituent amino acids.[37] Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibly oxidized and reduced. In cells, glutathione is maintained in the reduced form by the enzyme glutathione reductase and in turn reduces other metabolites and enzyme systems as well as reacting directly with oxidants.[32] Due to its high concentration and its central role in maintaining the cell's redox state, glutathione is one of the most important cellular antioxidants.[36]"
"As with the chemical antioxidants, cells are protected against oxidative stress by an interacting network of antioxidant enzymes.[8][7] 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 can be hard to separate from one another, but the generation of transgenic mice lacking just one antioxidant enzyme can be informative.[42]
Superoxide dismutases (SODs) are a class of closely related enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide.[43][44] SOD enzymes are present in almost all aerobic cells and in extracellular fluids.[45] Superoxide dismutase enzymes contain metal ion cofactors that, depending on the isozyme, can be copper, zinc, manganese or iron. In humans, the Cu/Zn SOD is present in the cytosol, while MnSOD is present in the mitochondrion.[44] There also exists a third form of SOD in extracellular fluids, termed EC-SOD, which contains copper and zinc in its active sites.[46] MnSOD seems to be the most biologically important of these three since mice lacking this gene die soon after birth.[47] Mice lacking CuZnSOD have lowered fertility, while EC-SOD lacking mice have minimal defects.[42][48]
Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor.[49][50] 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.[51] Despite its apparent importance in hydrogen peroxide removal, humans with genetic deficiency of catalase "acatalasemia" suffer few ill effects.[52][53]
Decameric structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium.
Decameric structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium.[54]
Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite.[55] They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins.[56] These enzymes share the same basic catalytic mechanism, in which an redox-active cysteine (the peroxidatic cysteine) in the active site is oxidized to a sulfenic acid by the peroxide substrate.[57] Peroxiredoxins seem to be important in antioxidant metabolism, as mice lacking peroxiredoxin 1 or 2 have shortened lifespan and suffer from hemolytic anaemia.[58][59]
The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase.[60] Proteins related to thioredoxin are present in all sequenced organisms except Tropheryma whipplei (the bacteria that cause Whipple's disease).[61] 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.[62] After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using NADPH as an electron donor.[63]
The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases and glutathione S-transferases.[36] 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 for life as mice lacking this enzyme have normal lifespans,[64] but are hypersensitive to induced oxidative stress.[65] In addition, the glutathione S-transferases are another class of glutathione-dependent antioxidant enzymes that show high activity with lipid peroxides.[66] These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism.[67]"
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The possible mechanisms of action of antioxidants were first explored thoroughly by Moreau and Dufraisse, who recognized that a substance with anti-oxidative activity is likely to be one that is itself readily oxidized.[5] Research into how vitamin E prevents the process of lipid peroxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by scavenging reactive oxygen species before they can damage cells.[6]
The oxidative challenge in biology
Structure of hydrogen peroxide, oxygen is shown in red and hydrogen in white.
Structure of hydrogen peroxide, oxygen is shown in red and hydrogen in white.
Further information: Oxidative stress
A paradox in metabolism is that while the vast majority of complex life requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species.[7] 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.[8][9] In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell.[8][7]
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-).[10] These molecules are unstable and highly reactive, and can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins.[8] Damage to DNA leads to mutations and cancer if not reversed by DNA repair mechanisms,[11][12] while damage to proteins causes enzyme inhibition and denaturation.[13]
The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.[14] In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.[15] 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 molecular oxygen and form the superoxide anion, instead of moving through the series of well-controlled reactions of the electron transport chain.[16]
Metabolites
Antioxidants are classified into two broad divisions, depending on whether they are soluble in water or lipids. In general, water-soluble antioxidants react with oxidants in the cell cytoplasm and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation.[8] These compounds may be synthesized in the body or obtained from the diet.[9] 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 throughout the body (see table below).
The relative importance and interactions between these different antioxidants is a complex area, with the various metabolites and enzyme systems having synergistic and interdependent effects on one another.[17][18] The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system.[9] The amount of protection provided by any one antioxidant therefore depends on its concentration, its reactivity towards the particular reactive oxygen species being considered, and the status of the antioxidants with which it interacts.[9] 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.
Role of oxidative stress in disease
Further information: Pathology, Free-radical theory of ageing
Oxidative stress is thought to contribute to the development of a wide range of human diseases including Alzheimer's disease,[68][69] Parkinson's disease,[70] the pathologies caused by diabetes,[71][72] rheumatoid arthritis,[73] and neurodegeneration in motor neurone diseases.[74] In may of these cases it is unclear if oxidants trigger the disease, or if they are produced as a consequence of the disease and cause the disease symptoms.[75] One case in which this link is particularly well-understood is the role of oxidative stress in cardiovascular disease. Here, low density lipoprotein (LDL) oxidation appears to trigger the process of atherogenesis, which results in atherosclerosis, and finally cardiovascular disease.[76][77]
A low calorie diet extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress.[78] While there is good evidence to support the role of oxidative stress in aging in model organisms such as Drosophila melanogaster and Caenorhabditis elegans,[79][80] the evidence in mammals is less clear.[81][82][83] Diets high in fruit and vegetables, which are high in antioxidants, promote health and reduce the effects of ageing, however antioxidant vitamin supplementation has no detectable effect on the ageing process, so the effects of fruit and vegetables may be unrelated to their antioxidant contents.[84][85]
[edit] Health effects
[edit] Uses in treatment of disease
The best-studied areas in which antioxidants are used as medication is in the treatment of various forms of brain injury. Here, superoxide dismutase mimetics,[86] sodium thiopental and propofol are used to treat reperfusion injury and traumatic brain injury,[87] while the experimental drug NXY-059[88][89] and ebselen[90] are being applied in the treatment of stroke. These compounds appear to prevent oxidative stress in neurons and prevent apoptosis and neurological damage. Antioxidants are also being investigated as possible treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.[91][92]
[edit] Uses in attempts to prevent disease
Structure of the polyphenol antioxidant resveratrol.
Structure of the polyphenol antioxidant resveratrol.
The evidence for the efficacy of antioxidants preventing diseases is mixed. While some studies have suggested that these compounds might preventing conditions such as macular degeneration,[93] suppressed immunity due to poor nutrition,[94] and neurodegeneration due to oxidative stress.[95] However, despite the celar role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no clear reduction in the risk of heart disease. This suggests that other substances in fruit and vegetables at least partially explain the better cardiovascular health of those who consume more fruit and vegetables.[96]
Many nutraceutical and health food companies now sell formulations of antioxidants as dietary supplements and these are widely used in industrialized countries.[97] These supplements may include specific antioxidant chemicals, like resveratrol (from grape seeds), combinations of antioxidants, like the "ACES" products that contain beta carotene (provitamin A), vitamin C, vitamin E and Selenium, or speciality herbs that are known to contain antioxidants such as green tea and jiaogulan. Although some levels of antioxidant vitamins and minerals in the diet are required for good health, there is considerable doubt as to whether antioxidant supplementation is beneficial, and if so, which and what amount of antioxidant(s) are optimal.[98][99]
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.[100] 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. However, none of these trials found a statistically significant effect of Vitamin E on overall number of deaths or on deaths due to heart disease.[101]
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.[102] 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 investigators found there was no statistically significant effect of the antioxidants on overall survival, cancer, or heart disease. However, a subgroup analysis showed a 31% reduction in the risk of cancer in men, but not women.
[edit] Physical exercise
During exercise, oxygen consumption can increase by a factor of more than 10.[103] 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 damage done by exercise peaks 2 to 7 days after exercise, the period during which adaptation resulting in greater fitness is greatest. During this process, free radicals are produced by neutrophils to remove damaged tissue. As a result, excessive antioxidant levels have the potential to inhibit recovery and adaptation mechanisms.[104]
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 deal with the increased oxidative stress.[105] It is possible that 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.[106]
However, no benefits to athletes are seen with vitamin A or E supplementation.[107] For example, despite its key role in preventing lipid membrane peroxidation, 6 weeks of vitamin E supplementation had no effect on muscle damage in ultramarathon runners.[108] Although there appears to be no incerased requirement for vitamin C in athletes, there is some evidence that supplementation with vitamin C increased the amount of intense exercise that can be done, vitamin C supplementation before strenuous exercise may reduce the amount of muscle damage.[109][110] However, other studies found no such effects, and some research suggests that supplementation with amounts as high as 1000 mg inhibits recovery,[111]
Structure of the metal chelator phytic acid.
Structure of the metal chelator phytic acid.
[edit] Adverse effects
Further information: Micronutrients
Relatively strong reducing acids can have anti-nutritional effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed.[112] Notable examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets.[113] Calcium and iron deficiencies are not uncommon in diets in developing counties where less meat is eaten and there is high consumption of phytic acid from beans and unleavened whole grain bread.[114]
Foods Reducing acid present
Cocoa and chocolate, spinach, turnip and rhubarb.[115] Oxalic acid
Whole grains, maize, legumes.[116] Phytic acid
Tea, beans, cabbage.[117][115] Tannins
Nonpolar antioxidants such as eugenol, a major component of oil of cloves have toxicity limits that can be exceeded with the misuse of undiluted essential oils.[118] 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.[119] 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 beta-carotene supplements had increased rates of lung cancer.[120] Subsequent studies confirmed these adverse effects in smokers given beta carotene.[121]
While antioxidants supplementation is widely hypothesized to prevent the development of cancer, antioxidants may, paradoxically, interfere with cancer treatments.[122] One explanation for this effect is that the growth-promoting environment of cancer cells leads to high levels of redox stress, making these cells more susceptible to the further 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.[123]
[edit] Measurement and levels in food
Tea is a rich source of antioxidants.
Tea is a rich source of antioxidants.[124]
Further information: List of antioxidants in food, Polyphenol antioxidants
Measurement of antioxidants is not a straightforward process, as this is a diverse group of compounds with different reactivities to different reactive oxygen species. In food science, the oxygen radical absorbance capacity (ORAC) has become the current industry standard for assessing antioxidant strength of whole foods, juices and food additives.[125][126] Other measurement tests include the Folin-Ciocalteu reagent, and the trolox equivalent antioxidant capacity assay.[127] In medicine, a range of different assays are used to assess the antioxidant capability of blood plasma and of these, the ORAC assay may be the most reliable.[128]
Antioxidants are found in varying amounts in foods such as vegetables, fruits, grain cereals, legumes and nuts. Some antioxidants such as lycopene are ascorbic acid can be destroyed by long-term storage or prolonged cooking.[129][130] Other antioxidant compounds are more stable, such as the polyphenolic antioxidants in foods such as whole-wheat cereals.[131] In general, processed foods contain less antioxidants than fresh and uncooked foods, since the preparation processes may expose the food to oxygen.[132] |
