US Pharm. 2008;33(10):HS-22-HS-28.
An antioxidant, or a free-radical scavenger, is a molecule capable of decreasing or preventing the oxidation of other molecules. Oxidation reactions transfer electrons from a substance to an oxidizing agent. During this process, some free-radicals are produced, which starts chain reactions that damage animal cells. Antioxidants slow down these chain reactions by removing free-radical intermediates and eventually inhibit other oxidation reactions by being oxidized themselves. Antioxidants often play the role of a reducing agent, e.g., thiols or polyphenols.1
Antioxidants are compounds of many different chemical structures and are classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). In general, water-soluble antioxidants react with oxidants in the cell cytoplasm and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation. These compounds may be biosynthesized or obtained from the diet. 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.1 In general, they either prevent the formation of free-radicals or neutralize those that are formed or repair the damage done by free-radicals. Using antioxidant supplements has not been generally proven to replace the use of natural or food-based antioxidants.
Oxidation reactions are crucial for life, but they can also be damaging; hence, all live plants and animals maintain a complex system of antioxidant enzymes such as catalase, superoxide dismutase, and various peroxidases, as well as other antioxidants, such as glutathione, vitamin C, and vitamin E. Low levels of antioxidants, or inhibition of the antioxidant enzymes, cause oxidative stress and may damage or kill cells.2
As oxidative stress might be an important part of many human diseases, the use of antioxidants in medicine is intensively studied, particularly as treatments for stroke and neurodegenerative diseases; however, it is not known whether oxidative stress is the cause or the consequence of disease. Antioxidants are widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease. Although some studies have suggested antioxidant supplements have health benefits, other large clinical trials did not detect major benefit for the formulations tested and found that excess supplementation may be harmful. In addition to their uses in medicine, antioxidants have many industrial uses, such as preservatives in food and cosmetics and preventing the degradation of materials such as rubber and gasoline.2
The atoms and molecules that make up our bodies have one or more pairs of electrons in their outer orbits. In the 1950s, scientists identified free-radicals as atoms or molecules that are missing one of two electrons, thus forming the free-radical molecules that seek to complete their structures. When a molecule or atom is missing one of its electrons, it becomes unstable and will try to take another electron from any other molecule in its immediate environment. If a free-radical acquires an electron from the molecule next to it, then that molecule or atom may become a free-radical. In turn, the next free-radical attacks a molecule next to it, and so on. Thus, there is a chain reaction of molecules that are desperately seeking completion, leaving severe damage in their surroundings wherever an electron pair is broken. The free-radicals are named troublemakers and originate mostly from reactive oxygen species.
The conversion of food to energy in our bodies is accomplished in organelles--tiny structures within our cells called mitochondria. The mitochondria may be thought of as little furnaces that take food that has been broken down into its basic chemical structure and then combine these chemicals with oxygen, producing water and energy. The problem is that about 5% of the energy produced turns into reactive oxygen species or free-radicals. In addition, free-radicals are created in very high levels throughout the body whenever there is trauma, infection, or inflammation. When we walk outside on a sunny day, the sunlight immediately begins to trigger free-radical formation, which causes damage to our skin and the tissue beneath it. Fortunately, nature has built-in-defense mechanisms against free-radicals. These defense systems are antioxidants, which prevent damage
The Oxidative Stress
An imbalance between the production of reactive oxygen species and biological systems' ability to readily detoxify these reactive intermediates causes oxidative stress. Many diseases, such as Alzheimer's, Parkinson's, some pathologies of diabetes, rheumatoid arthritis, and other diseases caused by neurodegeneration, are believed to develop due to oxidative stress. In many of these cases, it is unclear whether oxidants trigger the disease or whether they are produced as a consequence of the disease and cause the disease symptoms. It is known that low-density lipoprotein (LDL) oxidation appears to trigger the process of atherogenesis, which results in atherosclerosis and finally cardiovascular diseases.4
As mentioned earlier, while the vast majority of organisms require oxygen for their existence, oxygen is also a highly reactive molecule that damages living organisms by producing reactive oxygen species. Consequently, organisms contain a complex network of antioxidant and enzyme systems 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.
Some of the most important reactive oxygen species that are produced in cells are hydrogen peroxide (H2O2), hypochlorous acid (HClO), and free-radicals such as the hydroxyl radical (-OH) and the superoxide anion (O2-). All of these are by-products of several steps in the body's electron transfer mechanisms. The hydroxyl radical is very unstable and will react rapidly and nonspecifically with most biological molecules. These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation or by oxidizing DNA or proteins. Damage to DNA can cause mutations and possibly cancer if not reversed by DNA repair mechanisms, while damage to proteins causes enzyme inhibition, denaturation, and protein degradation.
Plants can also neutralize reactive oxygen species that are produced during photosynthesis by the involvement of their carotenoids in photoinhibition. Carotenoid antioxidants in turn react with overreduced forms of the photosynthetic reaction centers to prevent the production of reactive oxygen species.
A low-calorie diet extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress. Diets rich in fruit and vegetables, which are high in antioxidants, promote health and reduce the effects of aging; however, antioxidant vitamin supplementation has no detectable effect on the aging process, so the effects of fruit and vegetables on aging may be unrelated to their antioxidant content. One reason for this might be the fact that consuming antioxidant molecules such as polyphenols and vitamin E produces other metabolic changes, so it may be that these other nonantioxidant effects are important in human nutrition.5
Antioxidants' Cons and Pros
There is some evidence that antioxidants might help prevent diseases such as macular degeneration, suppressed immunity due to poor nutrition, and neurodegeneration. A number of observations suggest that antioxidants might help prevent these conditions; however, despite the clear role of oxidative stress in cardiovascular disease, controlled studies using antioxidant vitamins have observed no major reduction in either the risk of developing heart disease or the rate of progression of existing disease. As a result, these effects might be the result of other substances in fruit and vegetables (possibly flavonoids), or a complex mix of substances may contribute to the better cardiovascular health of those who consume more fruit and vegetables.
It is also believed that oxidation of LDL 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 supplementation with vitamin E, in doses ranging from 50 to 600 mg per day. Interestingly, none of these trials found a statistically significant effect of vitamin E on overall number of deaths or on deaths due to heart disease. Therefore, 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.6
Many nutraceutical and health food companies now sell formulations of antioxidants as dietary supplements, and these are widely used in industrialized countries. These supplements may include specific antioxidant chemicals, such as resveratrol (from grape seeds); combinations of antioxidants, like the ACES products that contain beta carotene (provitamin A), vitamin C, vitamin E, and Selenium; or herbs that contain antioxidants, such as green tea. Although some levels of antioxidant vitamins and minerals in the diet are required for good health, there is some doubt as to whether antioxidant supplementation is beneficial and, if so, which antioxidant(s) are beneficial and in what amounts.
The brain is uniquely vulnerable to oxidative injury due to its high metabolic rate and elevated levels of polyunsaturated lipids, the target of lipid peroxidation. Consequently, antioxidants are commonly used as medications to treat various forms of brain injury. Hence, superoxide dismutase mimetics, sodium thiopental, ascorbic acid, and propofol are used to treat reperfusion injury and traumatic brain injury. These compounds appear to prevent oxidative stress in neurons and prevent apoptosis and neurological damage.7
Total Antioxidant Capacity
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 the antioxidant strength of whole foods, juices, and food additives. Other measurement tests are the Folin-Ciocalteu reagent and the Trolox Equivalent antioxidant capacity assay. In medicine, a range of different assays are used to assess the antioxidant capability of blood plasma. Of these, the ORAC assay may be the most reliable.
Different foods have different quantities of antioxidants, and the total amount can be measured by chemical means. The total antioxidant capacity (TAC) is expressed in micromoles per 100 grams of food and equals Lipophilic-ORAC + Hydrophilic-ORAC. Different measurement methods, however, yield different results, and these are only relevant when used comparatively within the same batch of food. TAC is a useful quantitative analytical measure of antioxidant content, but it lumps together the good, the bad, and the positively harmful compounds loosely classified as antioxidants.
The Michelin Star Guide has been used to rank individual antioxidants (TABLE 1). This rating system is being extended to antioxidant classes and food items. No individual antioxidant has been awarded more than three stars. It will require combinations, metabolites, or the initiation of physiological antioxidants to achieve a four- and five-star ranking.8
Antioxidants and Physical Activity
During the peak of 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 heavy 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 two to seven days after exercise, the period during which the results of exercise to fitness is greatest. During this process, some of the body mechanisms try to remove damaged tissues, and excessive antioxidant levels have the potential to inhibit recovery and adaptation mechanisms.
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.9 It is possible that this effect may be to some extent protective against diseases that 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.
However, no benefits to athletes are seen with vitamin A or E supplementation. For example, despite its key role in preventing lipid membrane peroxidation, six weeks of vitamin E supplementation had no effect on muscle damage in serious runners. Although there appears to be no increased requirement for vitamin C in athletes, there is some evidence that vitamin C supplementation increases the amount of intense exercise that can be done and reduces muscle damage from heavy exercise. Other studies found no such effects, however, and some research suggests that supplementation with amounts as high as 1,000 mg inhibits recovery.10
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 is less of a concern, as these compounds can be excreted rapidly in urine. Very high doses of some antioxidants may have serious long-term effects. The Beta-Carotene and Retinol Efficacy Trial (CARET) study of patients with lung cancer found that smokers given supplements containing beta-carotene and vitamin A had increased rates of lung cancer. Subsequent studies also confirmed these adverse effects.11
While antioxidant supplementation is widely used in attempts to prevent the development of cancer, it has been proposed that antioxidants may, paradoxically, interfere with cancer treatments. This was thought to occur since the environment of cancer cells causes high levels of oxidative stress, making these cells more susceptible to the further oxidative stress induced by treatments. As a result, by reducing the redox stress in cancer cells, antioxidant supplements in very large doses were thought to decrease the effectiveness of radiotherapy and chemotherapy.12 This concern appears unfounded, however, because multiple clinical trials have reported that antioxidants are either neutral or beneficial in cancer therapy.11
Some antioxidants are made in the body but are not absorbed from the intestine. One 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.9 Coenzyme Q-10 is also poorly absorbed from the gut and is made in humans through the mevalonate pathway.13
1. Nordberg J, Arner ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med. 2001;31:1287-1312.
2. Imlay J. Pathways of oxidative damage. Annu Rev Microbiol. 2003;57:395-418.
3. Krieger-Liszkay A. Singlet oxygen production in photosynthesis. J Exp Bot. 2005;56:337-346.
4. Cherubini A, Vigna G, Zuliani G, et al. Role of antioxidants in atherosclerosis: epidemiological and clinical update. Curr Pharm Des. 2005;11:2017-2032.
5. Sohal R. Role of oxidative stress and protein oxidation in the aging process. Free Radic Biol Med. 2002;33:37-44.
6. Herrera E, Barbas C. Vitamin E: action, metabolism and perspectives. J Physiol Biochem. 2001;57:43-56.
7. Duarte TL, Lunec J. Review: when is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C. Free Radic Res. 2005;39:671-686.
8. Total Antioxidants of Common Foods. www.naturalantioxidants.org/Total_Antioxidants.html.
9. Hayes J, Flanagan J, Jowsey I. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45:51-88.
10. Clarkson PM, Thompson HS. Antioxidants: what role do they play in physical activity and health? Am J Clin Nutr. 2000;72:637S-646S.
11. Antioxidants and Cancer Prevention: Fact Sheet. National Cancer Institute. Accessed February 27, 2007.
12. Moss R. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr Cancer Ther.2006;5:63-82.
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