- A chemical compound or substance that inhibits oxidation.
- A substance, such as vitamin E, vitamin C, or beta carotene, thought to protect body cells from the damaging effects of oxidation.
antioxidant
Did you mean: antioxidant (in biochemistry), antioxidants
Dictionary:
an·ti·ox·i·dant (ăn'tē-ŏk'sĭ-dənt, ăn'tī-)  |
| Oncology Encyclopedia: Antioxidants |
Key Terms: Apoptosis, Cisplatin, Doxorubicin, Fluorouracil, Mutation.
Definition
Antioxidants are chemical compounds that can bind to free oxygen radicals preventing these radicals from damaging healthy cells.
Purpose
Preliminary studies have suggested that antioxidants are useful in a number of ways in regards to cancer. For instance, they may improve the effectiveness of chemotherapy, decrease side effects of chemotherapy and radiotherapy, and prevent some types of cancer. Sufficient epidemiological studies have shown that ingesting foods high in antioxidants, such as fruits and vegetables, can decrease the risk of many types of cancer. Studies also found that cancer patients have lower levels of anti-oxidants in their blood.
In early 2004, the National Cancer Institute (NCI) released a new fact sheet concerning cancer prevention and antioxidants. Fruits and vegetables are high in anti-oxidants and evidence continued to support the role of vitamins C, E, and A, as well as lycopene and beta-carotene in helping to prevent cancer. However, clinical trial results have not been consistent. The NCI reported that three large clinical trials were trying to better answer the role of antioxidants in cancer prevention.
Precautions
Studies of antioxidant supplements to decrease the risk of cancer have not been conclusive. Most antioxidant research has centered around vitamins A (and its provitamin, beta-carotene), C, E (alpha-tocopherol), and the trace element selenium. While some studies have shown positive effects for antioxidants in preventing cancer, they have been conducted mostly in underfed populations or persons otherwise deficient in these antioxidants. The CARET studies in the early 1990s found that if smokers take beta-carotene and vitamin A supplements they actually increase their risk of developing lung cancer. Rather than isolated antioxidants found in supplements, it may be the combination of antioxidants found in foods that are responsible for decreasing the risk of cancer. The American Institute of Cancer Research warns that antioxidant supplements cannot substitute for whole foods. Individuals who may want to consider supplements include those who are underfed, have certain medical conditions, chronic dieters, some vegetarians, some seniors, and newborns.
Concern has developed about potential negative interactions between high doses of antioxidants and chemotherapy. Anthracycline antitumor antibiotics used as chemotherapy act by creating free oxygen radicals to kill tumor cells through a process known as apoptosis. Although patients taking antioxidants may improve their tolerance to chemotherapy drugs, they may be decreasing the effectiveness of treatment and risking a recurrence of the tumor in the long run. This viewpoint is theoretical, however, and no clinical studies have as yet addressed it. Patients interested in using antioxidants during chemotherapy or radiotherapy should discuss this option with their physicians.
High doses of vitamins and minerals can be toxic. The National Academy of Sciences has suggested safe upper intake levels for adults for some antioxidants. These limits are 2,000 milligrams of vitamin C per day from both foods and supplements combined, 1,000 milligrams of vitamin E per day, and 400 micrograms per day of selenium from both supplements and foods. It is not known how higher levels than these will affect healthy persons.
Side effects of vitamin E overdose may include fatigue, intestinal cramping, breast soreness, thrombophlebitis, acne, and diarrhea, and increase in blood pressure in certain people. Blood clotting time has been shown to increase. Vitamin E is antagonistic to iron at certain levels. Patients with anemia who are taking iron supplements should not take the two supplements at the same time. Vitamin E also may interfere with vitamin K. Selenium toxicity is characterized by dermatologic lesions, brittle hair, fragile or black fingernails, metallic taste, dizziness, and nausea.
Description
Free radicals are naturally produced in the body through the normal metabolism of amino acids and fats. These free radicals are unstable molecules that can freely react with and destroy healthy cells. They can bind to and alter the structure of DNA thus leading to mutations and eventually to cancer. Besides cancer, this oxidative stress on the cells can lead to heart, eye, and neurological diseases.
Glutathione, lipoic acid, and CoQ10 are antioxidants formed naturally by the body but their levels decline with age. Vitamins C and E are necessary anti-oxidants but not produced by the body and must be obtained from the diet. The most common antioxidants are the vitamins A, C, and E. Additional antioxidants are natrol, found in grapes and wine; selenium; and melatonin. Flavonoids consist of a large family of antioxidant compounds found in fruits and vegetables. Among the well-studied flavonoids in terms of cancer prevention are catechins from green tea, genistein from soy, curcumin from turmeric, anthocyanosides from blueberries, and quercetin from yellow vegetables. More recent studies have added clack beans to the list of foods high in antioxidants and a 2003 study in Rome reported that women who ate dark chocolate showed some antioxidant benefits.
Although controversy will surround the topic of supplemental antioxidants for some time, there is little if any controversy that dietary levels of antioxidants are useful in preventing cancer. Because of this evidence, the American Cancer Society suggests five servings of fruits and vegetables each day.
Resources
Books
Moss, Ralph W. Antioxidants Against Cancer. Brooklyn, NY: Equinox Press, Inc., 2000.
Periodicals
"Chocolate's Dark Health Secret." Muscle & Fitness/Hers December 2003: 22.
Kelly, Kara M. "The Labriola/Livingston Article Reviewed." Oncology 13, no. 7 (1999): 1008-1011.
Labriola, Dan, and Robert Livingston. "Possible Interactions Between Dietary Antioxidants and Chemotherapy." Oncology 13, no. 7 (1999): 1003-1008.
Lamson, Davis W, and Matthew S. Brignall. "Antioxidants in Cancer Therapy: Their Actions and Interactions with Oncologic Therapies." Alternative Medicine Review 4, no. 5 (1999): 304-329.
"'Musical Fruit' Rich Source of Healthy Antioxidants; Black Beans Highest." Cancer Weekly December 23, 2003: 102.
"Update on Antioxidants." Nutrition Today January–February 2004: 25–31.
Organizations
American Institute for Cancer Research. 1759 R Street, NW, PO Box 97167, Washington, DC 20090-7167. (800)843-8114.
National Academy of Science.
Other
—Cindy Jones, Ph.D.; Teresa G. Odle
| Food and Nutrition: antioxidant |
A substance that retards the oxidative rancidity of fats in stored foods. Many fats, and especially vegetable oils, contain naturally occurring antioxidants, including vitamin E, which protect them against rancidity for some time. Synthetic antioxidants include propyl, octyl, and dodecyl gallates, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT). See also antioxidant nutrients; induction period.
| Food and Fitness: antioxidant |
Antioxidants are chemicals that mop up unstable products of metabolism, called free radicals, which can damage the body. Antioxidants include beta-carotene, and the vitamins A, C, and E. Certain trace elements, such as copper, manganese, selenium, and zinc, also have some antioxidant properties. In addition, phenols (non-alcoholic components of red wine) and many other non-nutrient antioxidants in many plants may act as antioxidants, preventing platelets from sticking together and reducing the risk of blood clots, but this is unproven.
There is strong evidence that the combined antioxidant properties of vitamins A, C, and E provide some protection against certain cancers, particularly those of the bowel and bladder, and against cardiovascular disease. The World Health Organization recommends that we aim for a daily intake of about 450 grams (1 lb) of fruit and vegetables, especially orange and yellow fruits such as carrots, apricots, and oranges, and green vegetables, such as broccoli, and spinach (perhaps the cartoon hero Popeye had the right idea after all!). A variety of nuts, seeds and their oils should also be eaten because they are rich sources of vitamin E. Exercisers tend to consume more oxygen than sedentary people and they may produce more free radicals. Research by sports scientists indicates that consuming extra vitamins C and E may protect muscle fibres from free radical damage.
Some antioxidants, such as synthetic vitamin E (alpha tocopherol), are added to fatty foods (for example, margarine made from sunflower oil) to stop the food from going rancid. See also free radicals.
| Food Lover's Companion: antioxidants |
Substances that inhibit oxidation in plant and animal cells. Culinarily, antioxidants help prevent food from becoming rancid or discolored. In the body, many scientists believe that antioxidants may contribute to reducing cancer and heart disease. Ascorbic acid (vitamin C), which is easily obtained from citrus fruits, is a well known natural antioxidant, as is vitamin E, which is plentiful in seeds and nuts. Antioxidants are also abundant in cruciferous vegetables such as broccoli and Brussels sprouts.
| Dental Dictionary: antioxidants |
n.pl
Agents that reduce or prevent oxidation, such as occurs in the deterioration of fats, oils, and nonprecious metals.
| Alternative Medicine Encyclopedia: Antioxidants |
Description
Antioxidants are a broad group of compounds that destroy single oxygen molecules, also called free radicals, in the body, thereby protecting against oxidative damage to cells. They are essential to good health and are found naturally in a wide variety of foods and plants, including many fruits and vegetables. Many antioxidants, either singly or in combination, are also available as over-the-counter nutritional supplements in tablet or capsule form. The most commonly used antioxidants are vitamin C, vitamin E, and beta carotene. Others include grape seed extract, vitamin A, selenium, and coenzyme Q10. It is unknown whether or not supplemental antioxidants provide the same benefits as those occurring naturally in foods, however.
General Use
In brief, antioxidants destroy free radicals in the body. Free radicals are byproducts of oxygen metabolism that can damage cells and are among the causes of many degenerative diseases, especially diseases associated with aging. They are also associated with the aging process itself. As a person ages, cell damage accumulates, and supplementing the diet with extra antioxidant-rich foods can help slow the oxidative damage done to cells. Scientific studies validate the role of antioxidants in preventing many diseases. Although studies have shown lower rates of cancer and heart disease in people who eat a recommended amount of fruits and vegetables, recent clinical studies have shown that supplementation of diet with antioxidant vitamin therapy does not lower risk of cardiovascular disease or certain other diseases.
Many herbs and medicinal plants are good natural sources of antioxidants. These include carrots, tomatoes, yams, leafy greens, blueberries, billberries, ginkgo biloba, garlic, and green tea, to name a few. A diet rich in vitamin C, vitamin E, and beta carotene may help reduce the risk of some cancers, heart disease, cataracts, and strokes.
Vitamin a
A study by the University of Arizona found that vitamin A has a protective affect against many types of cancer, according to Dr. Michael Colgan in his book, The New Nutrition. Vitamin A is a fat-soluble antioxidant found in animal products but can be made by the body from its precursor, beta carotene. Foods rich in vitamin A are liver, eggs, and fortified dairy products. Vitamin A helps bones and teeth develop, and promotes vision. As an antioxidant, it protects cell membranes and fatty tissue, helps repair damage caused by air pollutants, and boosts the immune system. A deficiency of this vitamin can result in dry skin, brittle hair, vision problems, blindness, and increased susceptibility to respiratory infections.
Vitamin C
Probably the most widely used of all vitamin supplements, vitamin C is a powerful antioxidant that has a myriad of functions and helps strengthen the immune system. It became famous in the 1970s when Nobel Prize-winning scientist Linus Pauling advocated daily mega doses (8-10 grams) of vitamin C to prevent and ease the symptoms of the common cold. Many clinical studies that show vitamin C is superior to over-the-counter medicines in reducing the symptoms, duration, and severity of colds. As an antioxidant, vitamin C may help fight cardiovascular disease by protecting the linings of arteries from oxidative damage. In 2002, debate still continued on the vitamin's effects on heart disease. One study revealed that Vitamins C and E helped reduce arteriosclerosis (hardening of the arteries) following heart transplants. Yet another study demonstrated that vitamin therapy had not effect on preventing heart disease. There is some evidence and research that vitamin C can help prevent cancer. Studies have shown it is also beneficial in protecting the body against the effects of smoking and air pollutants.
Vitamin E
Vitamin E is a potent antioxidant by itself, but its effectiveness is magnified when taken with other antioxidants, especially vitamin C, selenium, and beta carotene. Some scientific evidence indicates that vitamin E helps promote cardiovascular health. Past studies have demonstrated higher vitamin E intake is associated with decreased incidence of heart disease in both men and women. In fact, the combination of Vitamin C and E can slow progression of cardiovascular disease following heart transplant. In 2002, researchers stated that the vitamin combination might also be useful in other organ transplants. In addition, Harvard Medical School reported in the same year that Vitamin E might play a role in helping people live longer, citing its role in strengthening the immune system.
Carotenoids
This class of antioxidants includes beta carotene, lutein, and lycopene. They are found in a variety of fruits and vegetables such as carrots, pumpkins, kale, spinach, tomatoes, and pink grapefruit. Research evidence suggests carotenoids lower the risk of heart disease and some types of cancer, and strengthen the immune system. Lycopene, which is concentrated in the prostate gland, is believed to protect the prostate from cancer. Lutein is thought to prevent macular degeneration, a major cause of blindness, or stop its progression. Beta carotene increases the lungs' defense system in smokers or those exposed to other air-borne pollutants. It also has been used as an immune system stimulator in people with AIDS. In 2002, a report revealed that more than 90% of ophthalmologists and optometrists surveyed believe that lutein helps prevent eye disease.
Bioflavonoids
Bioflavonoids are a group of about 5,000 compounds that act as antioxidants. They occur in fruits, vegetables, green tea, soy products, herbs, and spices. A combination of bioflavonoids has a synergistic effect when taken with vitamin C. They have been shown to be beneficial in treating a variety of conditions, including allergies, arthritis, diabetes, hypertension, and viral infections. One group of bioflavonoids found to be a powerful antioxidant is oligomeric proanthocyanidins (OPCs), also known generically as pycnogenol. Extremely high concentrations of OPCs are found in maritime pine bark (Pinus maritima) extract, grape seed extract, and grape and peanut skins. Due primarily to its much lower cost, grape seed extract is the most commonly used OPC. Procyanidins, a group of compounds found in the extract, are thought to increase the effectiveness of other antioxidants, especially vitamin C and vitamin E, by helping them regenerate after neutralizing free radicals in the blood and tissue.
Other Antioxidants
The other widely used antioxidants are selenium, coenzyme Q10, and certain amino acids. Selenium, especially when teamed with vitamin E, may help protect against lung, colon, prostate, and rectum cancers. The antioxidant benefits of coenzyme Q10 may include slowing the aging process, boosting the immune system, and preventing oxidative damage to the brain. Some still suggest its use to treat a variety of cardiovascular diseases. Amino acids that have strong antioxidant effects include alpha lipoic acid, cysteine, glutathione, and N-acetyl cysteine (NAC).
Preparations
Bottled antioxidant formulae are available in a single pill or as part of a multivitamin. The usual dosages of antioxidants taken individually can vary widely. The United States Department of Agriculture (USDA) has established recommended daily allowance, but these may be conservative amounts for preventing diseases. For instance, the USDA recommendation for vitamin C is 60 mg a day but natural healthcare practitioners commonly recommend 500 mg a day or more. The dosage may also depend on whether it is being taken to treat or prevent a specific condition. With that in mind, the common daily dosages for specific antioxidants are: vitamin A, 5,000-15,000 IU; beta carotene, 15,000-25,000 IU; vitamin C, 250-1,500 mg; vitamin E, 30-400 IU; selenium, 50-400 micrograms; bioflavonoids, 100-500 mg; grape seed extract, 150-200 mg; coenzyme Q10, 90-150 mg; alpha lipoic acid, 20-50 mg or 300-600 mg for elevated blood sugar levels; glutathione, 100 mg; N-acetyl cysteine, 600 mg.
Precautions
Vitamin C: May interfere with some laboratory tests, including urinary sugar spilling for diabetics. Vitamin A: Can be toxic in high doses of more than 15,000 IU per day or chronic doses for months, and may cause birth defects if taken in high doses during pregnancy. In 2002, one study showed that consistent Vitamin A intake could increase the risk of hip fractures in postmenopausal women, but the study was not representative of all women, and more study on the upper limits of safe Vitamin A consumption for women in their 40s and 50s is needed. Vitamin E: Dangerous in very high doses. Carotenoids: No known precautions are indicated for normal doses. Bioflavonoids: No known precautions are indicated for normal doses. Selenium: No precautions indicated at normal doses, but a physician should be consulted before taking daily doses of more than 200 micrograms. Coenzyme Q10: No known precautions are indicated for normal dosage. Amino acids: There are no known precautions indicated for alpha lipoic acid, cysteine, glutathione, or NAC.
Side Effects
Vitamin C: Individual tolerances vary. High doses may cause cramps, diarrhea, ulcer flare-ups, kidney stones, and gout in some people. Vitamin A: High doses can lead to headaches, nausea, hair loss, and skin lesions; may cause bone disease in people with chronic kidney failure. Vitamin E: Usually no adverse side effects in doses of up to 400 mg a day, high doses may elevate blood pressure and lead to blood-clotting problems. Carotenoids: No known side effects occur with normal dosage. Bioflavonoids: No known negative side effects in normal doses. Selenium: No reported adverse side effects with normal dosage of 200 micrograms, higher doses may cause dizziness and nausea. Coenzyme Q10: No adverse side effects have been reported. Amino acids: There are no known side effects associated with normal doses of alpha lipoic acid, cysteine, glutathione, or NAC.
Interactions
Vitamin C: No known common adverse interactions with other drugs. Vitamin A: Women taking birth control pills should consult with their doctors before taking extra vitamin A. Vitamin E: Should not be used by persons taking anti-coagulation drugs. Carotenoids: No known negative interactions with other drugs. Bioflavonoids: No known adverse interactions with other drugs. Coenzyme Q10: No negative drug interactions yet reported. Amino acids: There are no adverse reactions yet reported between alpha lipoic acid, cysteine, glutathione, or NAC and other medications.
Resources
Books
Balch, Dr. James F. The Super Antioxidants: Why They Will Change the Face of Health Care in the 21st Century. M. Evans and Co., 1998.
Colgan, Dr. Michael. The New Nutrition. CI Publications, 1996.
Challem, Jack, editor. All About Antioxidants. Avery Publishing Group, 1999.
Hendler, Dr. Sheldon Saul The Doctors'Vitamin and Mineral Encyclopedia. Simon and Shuster, 1990.
Moss, Ralph W. Antioxidants Against Cancer. Equinox Press, 2000.
Murray, Michael T. Natural Alternatives to Over-the-Counter and Prescription Drugs. William Morrow and Co., 1994.
Packer, Lester, et al. The Antioxidant Miracle: Your Complete Plan For Total Health and Healing. John Wiley and Sons, 1999.
Smythies, John R. Every Person's Guide to Antioxidants Rutgers University Press, 1998.
Periodicals
Abramowiez, Dr. Mark, editor. "Vitamin Supplements." The Medical Letter (July 31, 1998): 75-77.
"Antioxidant Vitamin E Reported to Strengthen Immune System." Obesity, Fitness & Wellness Week (March 2, 2002): 12.
Fang, James C., et al. "Effect of Vitamins C and E on Progression of Transplant-Associated Arteriosclerosis: A randomized Trial." The Lancet (March 30, 2002): 1108.
Kiningham, Robert."The Value of Antioxidant Vitamin Supplements." American Family Physician (Sept. 1, 1999): 742.
Koch Kubetin, Sally. "Antioxidants Fall Short." OB GYN News (February 1, 2002): 29.
Langer, Stephen."Antioxidants: Our Knights in Shining Armor." Better Nutrition (May 1997): 46-50.
"Lutein Helps Protect Eyes, Doctors Say in Survey." Ophthalmology Times (March 15, 2002): 29.
Raloff, Janet."The Heart-Healthy Side of Lycopene." Science News (Nov. 29, 1997): 348.
Scheer, James F. "Twelve Key Antioxidants: May Their Force Be With You." Better Nutrition (Jan. 1999): 58.
Schindler, Martha."The Magnificent Seven." Vegetarian Times (Feb. 1999): 86.
"Simvastatin Yes, Antioxidant No ñ Two Important New Studies." Clinical Cardiology Alert (January 2002): 1.
Tyler, Varro E."The Miracle of Anti-Aging Herbs." Prevention (Nov. 1999): 105.
"Vitamin A Intake Levels Reaffirmed as Safe and Beneficial." Medical Letter on the CDC & FDA (January 27, 2002): 14.
[Article by: Ken R. Wells; Teresa G. Odle]
| Britannica Concise Encyclopedia: antioxidant |
For more information on antioxidant, visit Britannica.com.
| Sports Science and Medicine: antioxidant |
A compound, usually organic, that prevents or retards oxidation by molecular oxygen of materials such as food. Some antioxidants, such as beta carotene, selenium and vitamin C, may provide some protection against cancer because they neutralize free radicals.
| Columbia Encyclopedia: antioxidant |
antioxidant, substance that prevents or slows the breakdown of another substance by oxygen. Synthetic and natural antioxidants are used to slow the deterioration of gasoline and rubber, and such antioxidants as vitamin C (ascorbic acid), butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA) are added to foods (see food additives) to prevent them from becoming rancid or from discoloring.
In the body, nutrients such as beta-carotene (a vitamin A precursor), vitamin C, vitamin E, and selenium have been found to act as antioxidants. They act by scavenging free radicals, molecules with one or more unpaired electrons, which rapidly react with other molecules, starting chain reactions in a process called oxidation. Free radicals are a normal product of metabolism; the body produces its own antioxidants (e.g., the enzyme superoxide dismutase) to keep them in balance. However, stress, aging, and environmental sources such as polluted air and cigarette smoke can add to the number of free radicals in the body, creating an imbalance. The highly reactive free radicals can damage healthy DNA and have been linked to changes that accompany aging (such as age-related macular degeneration, a leading cause of blindness in older people) and with disease processes that lead to cancer, heart disease, and stroke.
Studies have suggested that the antioxidants that occur naturally in fresh fruits and vegetables have a protective effect. For example, vitamin E and beta-carotene appear to protect cell membranes; vitamin C removes free radicals from inside the cell. There is still some question as to whether antioxidants in the form of dietary supplements counteract the effects of increased numbers of free radicals in the body. Some scientists believe that regular consumption of such supplements interferes with the body's own production of antioxidants.
| Food & Culture Encyclopedia: Antioxidants |
Antioxidants are specific organic compounds that are active in the prevention of very rapid harmful chemical chain reactions with oxygen or nitric oxide, that is, oxidation reactions. In the body, oxidation reactions generally involve highly reactive molecules called free radicals. Free radicals reside primarily in the mitochondria of cells. When free radicals are released from the mitochondria in numbers sufficient to overwhelm the protective biochemical systems of the body, they become a threat to some cellular structures such as lipids, proteins, carbohydrates, and nucleic acids in cell membranes. Compromised cellular structure alters cellular function, and may lead to the initiation of the disease process. In severe oxidative stress, cell death may occur. Antioxidants react with the free radicals before they are able to react with other molecules, thus providing protection from oxidation reactions (Cross et al.).
Chemistry 101: How and Why Cells and Other Molecules Interact
The human body is made up of many different types of cells that are composed of multiple diverse types of molecules. Molecules are put together in such a way that one or more atoms of one or more elements are joined by chemical bonds. Atoms have a nucleus of neutrons and protons which is surrounded by electrons. It is the number of protons (positively charged particles) in the nucleus of the atom that determines the number of orbiting electrons (negatively charged particles). Electrons are involved in chemical reactions and are the substances that bond atoms together to form molecules. Electrons orbit the atom in one or more of the atom's shells. The innermost shell is full when it has two electrons. When the first shell is full, electrons begin to fill the second shell. When the second shell has eight electrons, it is full, and electrons begin to fill the third shell, and so on. The electrons surrounding antioxidants react with the electrons surrounding free radicals, causing them to become much less reactive. Antioxidants may be more effective when one antioxidant is used in combination with another. This synergistic relationship between several antioxidants occurs when, for example, vitamin E donates an electron from its outer shell to a free radical and vitamin C donates an electron to vitamin E, maintaining the ability of vitamin E to continue donating electrons to free radicals. Vitamin C may then receive an electron from glutathione that would enable vitamin C to remain active as an antioxidant. Therefore in this type of situation, an attack on membranes by a free radical results in the participation of three different antioxidants.
In What Forms Are Antioxidants Found and How Are They Metabolized?
Antioxidants are found in many forms. The principal vitamins with antioxidant properties are vitamins E and C, and beta-carotene. Vitamin E (d-alpha tocopherol) is a fat-soluble antioxidant, which means it is stored in body fat and works within the lipid portion of cell membranes to provide an alternative binding site for free radicals, preventing the oxidation of polyunsaturated fatty acids (Chow). Vitamin E is a family of eight compounds synthesized by plants in nature: four tocopherols (alpha, beta, gamma, delta) and four tocotrienols (alpha, beta, gamma, delta). Each has different levels of bioactivity in the body over quite a wide range, but generally speaking, alphatocopherol has greater bioactivity than beta-tocopherol, which has greater bioactivity than gamma-tocopherol, which has greater bioactivity than delta-tocopherol. Only alpha-tocotrienol has bioactivity of any significant amount, which is slightly less than that of beta-tocopherol. Digestion and absorption of vitamin E is greatly improved when consumption is accompanied with dietary lipids or fats. Absorption of vitamin E ranges from 20 to 50 percent, but may be as high as 80 percent, with absorption decreasing as intake increases (Bender, 1992). Dietary vitamin E absorption requires bile and pancreatic enzymes in the small intestine, where it is incorporated into micelles within the lumen of the small intestine. The micelles carry the vitamin E across the brush border of the small intestine and the vitamin E is then taken up by chylomicrons, which are transported by the lymph system to tissues and the liver. Vitamin E may be stored in the liver, adipose tissues, and skeletal muscle. When needed, vitamin E places itself in cell membranes. Excretion of vitamin E is by way of urine, feces, and bile (Wardlaw and Kessel).
Vitamin C (ascorbic acid) is a water-soluble antioxidant and is found in the water compartments of the body where it interacts with free radicals. It has been shown that short-term supplementation of vitamin C lasting two to four weeks can significantly reduce the level of free radicals in the body (Naidoo and Lux). Dietary vitamin C is absorbed primarily by active transport in the small intestine, with absorption decreasing as intake increases. Approximately 70 to 90 percent of vitamin C is absorbed when dietary intake is between 30 and 180 mg/day. The kidneys excrete excess dietary vitamin C in urine, but excrete virtually no vitamin C when intake of the vitamin is very low (Wardlaw and Kessel). After absorption in the small intestine, vitamin C is transported in the blood to cells in its reduced form, ascorbic acid or ascorbate. The concentration of vitamin C varies in different tissues in the body. For instance, vitamin C concentrations are highest in the adrenal and pituitary glands, intermediate in the liver, spleen, heart, kidneys, lungs, pancreas, and white blood cells, and lowest in the muscles and red blood cells (Olson and Hodges). This vitamin may also possess some prooxidant properties, meaning it can participate in oxidizing other molecules such as iron in the blood stream (Alhadeff et al.).
Beta-carotene is a precursor to vitamin A (retinol). Beta-carotene is the most widely known compound in a group known as carotenoids, which are pigment materials in fruits and vegetables that range from yellow to orange to red in color. Carotenoids are also called proformed vitamin A because they can be made into vitamin A by the body when necessary. Carotenoids are pigments that are responsible for the orange color of many fruits and vegetables such as oranges and squash. Other carotenoids present in foods include antheraxanthin, lutein, zeaxanthin, and lycopene. Dietary retinol is usually found bound to fatty acid esters, which are in turn bound to proteins, and must undergo a process called hydrolysis that frees the retinol from the esters, enabling the retinol to then be absorbed in the small intestine. Proteolytic enzymes in the small intestine, such as pepsin, hydrolyze the retinol from the proteins. Approximately 70 to 90 percent of dietary retinol is absorbed provided there is adequate (10 grams or more) fat in the meal consumed (Olson). Carotenoids are absorbed at much lower levels, sometimes at levels as low as 3 percent, with absorption decreasing as intake increases (Brubacher and Weisler). Retinol and the carotenoids are carried through the absorptive cells of the small intestine by micelles for transport through the lymph system to the liver, which then can "repackage" the vitamins to send to other tissues, or act as the storage facility for the vitamins until needed by the body.
There are also enzymes that possess antioxidant properties. Glutathione peroxidase, superoxide dismutase, and catalase are the most well known. Glutathione peroxidase breaks down peroxidized fatty acids, converting them into less harmful substances. Peroxidized fatty acids tend to become free radicals, so the action of glutathione peroxidase serves to protect cells. The activity of glutathione peroxidase is dependent on the mineral selenium, which is the functional part of this enzyme, or the part of the enzyme that makes it have antioxidant activity. Therefore, selenium is considered to have antioxidant properties. Superoxide dismutase and catalase react with free radicals directly, reducing their ability to oxidize molecules and cause cellular damage.
A class of compounds termed isoflavones, which are derived from soy, also have antioxidant activity. Genistein, daidzein, and prunectin are all able to prevent the production of free radicals. Isoflavone activity as an antioxidant plays an important role in the aging process and cancer prevention primarily due to having estrogenrelated biologic activities in humans (Shils et al.).
The polyphenols (epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate) found in jasmine green tea also possess natural antioxidant properties. Studies have shown that these polyphenols are able to protect red blood cells from destruction upon attack by free radicals (Shils et al.). The polyphenols present in red wine have also been found to be protective against the oxidation of low-density lipoproteins and high-density lipoproteins, which are very important factors in the prevention of the development of atherosclerosis or coronary artery disease (Ivanov et al.).
A final group of compounds, synthetic antioxidants, are often added to foods to prevent discoloration and delay oxidation of the foods after exposure to oxygen. They also help protect fats from rancidity. Rancidity causes fats to develop an unappealing flavor and odor. Most of the antioxidants used in foods are phenolic compounds. There are four antioxidants that are approved for use in foods, particularly fats. They are propyl gallate (PG), tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) (Charley and Weaver). Sulfites, which are sulfur-based chemicals, are also used as antioxidants in foods. However, because some people may be very sensitive to sulfites and have adverse reactions to them in foods, the Food and Drug Administration has required that labels on foods containing sulfites alert the public to their presence.
Dietary Sources of Antioxidants
Vitamin E is found in egg yolks, milk, plant and vegetable oils (including margarine and to a lesser extent butter), nuts, seeds, fortified whole-grain cereals, flatfish, halibut, shrimp, canned tuna in oil, asparagus, peas, tomatoes, apples, canned apricots in light syrup, blueberries, grapefruit, oranges, peaches, and pears. The milling process of whole grains causes most of the dietary vitamin E to be lost. The Recommended Dietary Allowance (RDA) as established by the U.S. Department of Agriculture currently is 15 International Units (IU) per day for men and 12 IU/day for women. In order for toxic effects to be produced, the amount of vitamin E consumed from foods would have to be 15 to 100 times the amount recommended for humans and this is extremely unlikely to occur (Wardlaw and Kessel). Symptoms and effects of toxicity are discussed in detail in Signs and Symptoms of Antioxidant Deficiency and Toxicity, below.
Vitamin C is present in large amounts in broccoli, asparagus, cabbage, cauliflower, potatoes, tomatoes, apples, applesauce, apricots, bananas, blueberries, cherries, grapefruit, lemons, oranges, peaches, strawberries, kiwi, pineapples, pears, cranberries, and the juices and jams made from these fruits. The Recommended Dietary Allowance for vitamin C currently is 60 mg/day for both males and females. Vitamin C obtained from foods rarely can be consumed in amounts large enough to be toxic to humans (Wardlaw and Kessel).
Beta-carotene is found in liver (primary storage organ in animals for vitamin A), egg yolk, fortified milk, butter, spinach, carrots, squash, sweet potatoes, broccoli, tomatoes, peaches, mangoes, apricots, papaya, cantaloupes, and fortified breakfast cereals. Because beta-carotene is converted to vitamin A by the body, there is no set requirement. However, the RDA for vitamin A is set in Retinol Equivalents (RE) at the level of 625 μg/day RE for men and 500 μg/day RE for women (Wardlaw and Kessel).
Diets High or Low in Antioxidants
Diets that are rich in antioxidants focus on high intakes of a variety of foods, especially large amounts of fruits, vegetables, and foods made from whole grains. Vegetarian diets, especially vegan diets (diets that exclude all foods from animal sources), are made up primarily from fruits, vegetables, whole grains, and legumes, and are an example of the types of diets that incorporate high levels of antioxidants. Another example of a diet that provides optimal levels of antioxidants is the Mediterranean diet. The Mediterranean diet is based on traditional eating habits in Greece, southern Italy, and Crete. This diet is rich in olive oil, foods from whole grains, and tomatoes, and minimizes the daily intake of poultry, eggs, sweets, and red meat. Red wine often accompanies meals in the Mediterranean diet and possesses some antioxidant activity (Murcia and Martinez-Tome). Furthermore, many of the spices used in Mediterranean cooking also have been observed to have some level of antioxidant properties (Martinez-Tome et al.). Asian-American diets also focus primarily on fruits, legumes, nuts, seeds, vegetables, and whole-grain food products, with liberal use of vegetable oils, while a minimum of meat is eaten. The traditional healthy Latin American diet provides beans, whole grains, nuts, fruits, and vegetables at every meal, with fish or shellfish, milk products, plant oils, and poultry being optional for daily intake.
Unfortunately, the typical American diet does not involve adequate intakes of fruits, vegetables, and whole-grain food products. This is not due to the lack of foods that fall into those categories but rather to the fact that too many Americans prefer fast foods and processed foods that are not rich sources of antioxidants. The Food Guide Pyramid developed by the United States Department of Agriculture recommends that six to eleven servings of bread cereal, rice, and pasta be consumed daily; three to five servings of vegetables per day; two to four servings of fruit per day; two to three servings of milk products per day; two to three servings of meat, poultry, fish, dry beans, eggs, and nuts per day; and that the use of fats, oils, and sweets be sparse (Wardlaw and Kessel). Most Americans do not adhere to the guidelines of the Food Guide Pyramid and therefore do not receive adequate amounts of foods that provide large quantities of antioxidants.
Certain disease states make it difficult to obtain adequate amounts of fat-soluble vitamins due to an inability to digest foods with fat properly. The digestion and absorption of fat in foods is required for digesting and absorbing fat-soluble vitamins such as vitamins A and E. Individuals with cystic fibrosis, celiac disease, and Crohn's disease absorb fat very poorly, which also means that the fat-soluble vitamins are poorly absorbed. As the unabsorbed fat passes through the small and large intestine, it carries the fat-soluble vitamins along with it, and is eventually excreted in the feces (Wardlaw and Kessel). Chronic alcoholics are also at risk for not obtaining adequate amounts of antioxidants due to a marked decrease in food intake in favor of the consumption of alcohol. Alcoholism may also result in liver disease, which leads to an inability of the liver to store the fat-soluble antioxidants.
Signs and Symptoms of Antioxidant Deficiency and Toxicity
Obtaining dietary intakes of vitamin E, vitamin C, and vitamin A from foods to meet the recommendations of the Food Guide Pyramid will prevent most healthy individuals from experiencing any deficiencies of these antioxidants. However, in diets that do not provide adequate amounts of fruits, vegetables, and whole grains, deficiencies may occur. It takes longer to develop a deficiency of the fat-soluble antioxidants, vitamins E and A, than it does to develop a deficiency of the water-soluble vitamin C.
Failure to obtain adequate vitamin E in the diet may cause certain medical conditions. Hemolytic anemia is caused by vitamin E deficiency, with an increased breakdown of red blood cells or hemolysis. Premature infants are most susceptible to vitamin E deficiency due to very small stores of the vitamin at birth and the frequently required use of oxygen to accommodate immature lungs. Premature infants are also growing very rapidly and need increased intakes of vitamin E. Special formulas are used to provide vitamin E to help prevent deficiency (Wardlaw and Kessel).
The disease caused by vitamin C deficiency is scurvy. The symptoms of scurvy are fatigue and small, purple spots or hemorrhages (petechiae) that appear around hair follicles on the back of the arms and legs. There are also bleeding gums and joints, impaired wound healing, pain in the bones, fractures, and diarrhea. Consuming a vitamin C–free diet for as little as 20 days may cause scurvy, but resuming vitamin C intake for one week can cause the reversal of the disease and accompanying symptoms (Wardlaw and Kessel).
Vitamin E toxicity may result from intakes of more than 1,500 IU/day of vitamin E isolated from natural sources and 1,100 IU/day for synthetic vitamin E for adults nineteen years or older. It is only possible to acquire such high doses of either form of vitamin E via supplementation. Use of supplemental vitamin E at such high doses in persons with a compromised health status may lead to complications such as hemorrhaging in individuals who are taking anticoagulants or are vitamin K-deficient (vitamin K is important in blood coagulation) (Wardlaw and Kessel).
Vitamin C toxicity may occur at intakes of 2 g/day or higher. The symptoms of vitamin C toxicity are nausea, abdominal cramps, and osmotic diarrhea. Because vitamin C is a water-soluble vitamin, much of excess vitamin C obtained from supplemental megadoses is excreted in urine (Wardlaw and Kessel).
Small children who do not eat enough vegetables are at an increased risk for vitamin A deficiency. In fact, individuals with very low incomes and the elderly are also at risk for deficiency due to an inability to obtain adequate intakes of foods that are good sources of vitamin A and to the decreased gastrointestinal function that may occur with age. Night blindness is a symptom of vitamin A deficiency, causing the rod cells in the eye to take a longer period of time to recover from flashes of light. Another symptom of vitamin A deficiency is dry eyes caused by deterioration of the mucus-forming cells in the body. In an individual with dry eyes, dirt and other contaminants are not washed away, and this may lead to eye infections. If vitamin A deficiency is not corrected, the condition of the eyes worsens, leading to more serious disorders of the eye; eventually irreversible blindness may result. The skin is also affected by a compromised vitamin A status. Primary symptoms are very dry skin and rough and bumpy texture of the skin surface. When vitamin A supplements are taken long-term at three times the RDA a condition called hypervitaminosis A may develop. This condition can cause spontaneous abortions in pregnant women or birth defects in infants and therefore women of child-bearing age wishing to become pregnant should avoid using high doses of vitamin A supplements (Wardlaw and Kessel).
Maintaining Antioxidant Content in the Foods You Eat
Antioxidants in foods are a valuable addition to a healthy diet and steps can be taken to preserve the antioxidant content of foods until they are ready to be ingested. Keeping fruits and vegetables refrigerated or in a cool, dry place helps to slow down the natural breakdown by enzymes that begins to occur as soon as the foods are picked. Fruits and vegetables should not be trimmed or cut until they are ready to be consumed to prevent unnecessary exposure to oxygen. Cooking by steaming, microwaving, or stir-frying in small amounts of fat for short amounts of time also helps to preserve the vitamin content of foods. If liquids are used to cook fruits or vegetables, do not add fat while cooking if you are planning to discard the liquid before eating the fruits or vegetables, to avoid losing the fat-soluble vitamins that may be in the liquids. Finally, it is important to remember that the skin of some fruits and vegetables contains a higher vitamin content than the inner parts, such as the skin of an apple (Wardlaw and Kessel).
Bibliography
Alhadeff, L., C. Gualtieri, and M. Lipton. "Toxic Effects of Water-Soluble Vitamins." American Journal of Clinical Nutrition 42 (1984): 33–40.
Bender, D. Nutritional Biochemistry of the Vitamins. New York: Cambridge University Press, 1992.
Brubacher, G., and H. Weisler. "The Vitamin A Activity of Beta-carotene." International Journal of Vitamin and Nutrition Research 55 (1985): 5–15.
Charley, H., and C. Weaver. Foods: A Scientific Approach. Upper Saddle River, N.J.: Prentice-Hall, 1998.
Chow, C. K. "Vitamin E and Oxidative Stress." Free Radical Biology and Medicine 11 (1991): 215–232.
Cross, C. E., A. vander Vliet, and C. O'Neil. "Reactive Oxygen Species and the Lung." Lancet 344 (1994): 930–933.
Ivanov, V., A. C. Carr, and B. Frei. "Red Wine Antioxidants Bind to Human Lipoproteins and Protect Them from Metal Ion-Dependent and -Independent Oxidation." Journal of Agricultural and Food Chemistry 49(9) (2001): 4442–4449.
Martinez-Tome, M., A. M. Jimenez, S. Ruggieri, N. Frega, R. Strabbioli, and M. A. Murcia. "Antioxidant Properties of Mediterranean Spices Compared with Common Food Additives." Journal of Food Protection 64(9) (2001): 1412–1419.
Murcia, M. A., and M. Martinez-Tome. "Antioxidant Activity of Resveratrol Compared with Common Food Additives." Journal of Food Protection 64(3) (2001): 379–384.
Naidoo, D., and O. Lux. "The Effect of Vitamin C and E Supplementation on Lipid and Urate Oxidation Products in Plasma." Nutrition Research 18 (1998): 953–961.
Olson, J. "Recommended Dietary Intakes (RDI) of Vitamin A in Humans." American Journal of Clinical Nutrition 45 (1987): 704–716.
Olson, A., and R. Hodges. "Recommended Dietary Intakes (RDI) of Vitamin A in Humans." American Journal of Clinical Nutrition 45 (1987): 693–703.
Shils, M. E., J. A. Olson, M. Shike, and A. C. Ross. Modern Nutrition in Health and Disease. Baltimore: Williams & Wilkins, 1999.
Wardlaw, G. M., and M. Kessel. Perspectives in Nutrition. Boston: McGraw-Hill, 2002.
—Rebecca J. (Bryant) McMillian
| Wine Lover's Companion: antioxidant |
In winemaking, reference to additives such as ascorbic acid and sulfur dioxide. When added in the right quantities, these substances limit the effect of oxygen contact with wine during various winemaking processes such as racking, filtering and bottling.
| Veterinary Dictionary: antioxidant |
A substance that in small amount will inhibit the oxidation of other compounds. Used in feeds and foods to prevent rancidification of polyunsaturated fats.
| Wikipedia: Antioxidant |
An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols, ascorbic acid or polyphenols.[1]
Although oxidation reactions are crucial for life, they can also be damaging; hence, plants and animals maintain complex systems of multiple types of antioxidants, such as glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases. Low levels of antioxidants, or inhibition of the antioxidant enzymes, causes oxidative stress and may damage or kill cells.
As oxidative stress might be an important part of many human diseases, the use of antioxidants in pharmacology is intensively studied, particularly as treatments for stroke and neurodegenerative diseases. However, it is unknown whether oxidative stress is the cause or the consequence of disease. Antioxidants are also widely used as ingredients in dietary supplements in the hope of maintaining health and preventing diseases such as cancer and coronary heart disease. Although initial studies suggested that antioxidant supplements might promote health, later large clinical trials did not detect any benefit and suggested instead that excess supplementation may be harmful.[2] In addition to these uses of natural antioxidants in medicine, these compounds have many industrial uses, such as preservatives in food and cosmetics and preventing the degradation of rubber and gasoline.
Contents |
History
The term antioxidant originally was used to refer specifically to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th century, extensive study was devoted to the uses of antioxidants in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerization of fuels in the fouling of internal combustion engines.[3]
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.[4] 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.[5][6]
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.[7] 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.[8]
The oxidative challenge in biology
Further information: Oxidative stress
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.[9] 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.[1][10] In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell.[1][9] However, since reactive oxygen species do have useful functions in cells, such as redox signaling, the function of antioxidant systems is not to remove oxidants entirely, but instead to keep them at an optimum level.[11]
The reactive oxygen species produced in cells include hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and free radicals such as the hydroxyl radical (·OH) and the superoxide anion (O2−).[12] 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.[13] These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins.[1] Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms,[14][15] while damage to proteins causes enzyme inhibition, denaturation and protein degradation.[16]
The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.[17] In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.[18] 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.[19] Peroxide is also produced from the oxidation of reduced flavoproteins, such as complex I.[20] However, although these enzymes can produce oxidants, the relative importance of the electron transfer chain to other processes that generate peroxide is unclear.[21][22] In plants, algae, and cyanobacteria, reactive oxygen species are also produced during photosynthesis,[23] particularly under conditions of high light intensity.[24] This effect is partly offset by the involvement of carotenoids in photoinhibition, which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species.[25][26]
Metabolites
Overview
Antioxidants 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 cytosol and the blood plasma, while lipid-soluble antioxidants protect cell membranes from lipid peroxidation.[1] These compounds may be synthesized in the body or obtained from the diet.[10] 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.[27]
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.[28][29] The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system.[10] 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.[10]
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.[30] 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.
| Antioxidant metabolite | Solubility | Concentration in human serum (μM)[31] | Concentration in liver tissue (μmol/kg) |
|---|---|---|---|
| Ascorbic acid (vitamin C) | Water | 50 – 60[32] | 260 (human)[33] |
| Glutathione | Water | 4[34] | 6,400 (human)[33] |
| Lipoic acid | Water | 0.1 – 0.7[35] | 4 – 5 (rat)[36] |
| Uric acid | Water | 200 – 400[37] | 1,600 (human)[33] |
| Carotenes | Lipid | β-carotene: 0.5 – 1[38] | 5 (human, total carotenoids)[40] |
| α-Tocopherol (vitamin E) | Lipid | 10 – 40[39] | 50 (human)[33] |
| Ubiquinol (coenzyme Q) | Lipid | 5[41] | 200 (human)[42] |
Ascorbic acid
Ascorbic acid or "vitamin C" is a monosaccharide antioxidant found in both animals and plants. As one of the enzymes needed to make ascorbic acid has been lost by mutation during human evolution, it must be obtained from the diet and is a vitamin.[43] Most other animals are able to produce this compound in their bodies and do not require it in their diets.[44] In cells, it is maintained in its reduced form by reaction with glutathione, which can be catalysed by protein disulfide isomerase and glutaredoxins.[45][46] Ascorbic acid is a reducing agent and can reduce and thereby neutralize reactive oxygen species such as hydrogen peroxide.[47] In addition to its direct antioxidant effects, ascorbic acid is also a substrate for the antioxidant enzyme ascorbate peroxidase, a function that is particularly important in stress resistance in plants.[48] Ascorbic acid is present at high levels in all parts of plants and can reach concentrations of 20 millimolar in chloroplasts.[49]
Glutathione
Glutathione is a cysteine-containing peptide found in most forms of aerobic life.[50] It is not required in the diet and is instead synthesized in cells from its constituent amino acids.[51] 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, such as ascorbate in the glutathione-ascorbate cycle, glutathione peroxidases and glutaredoxins, as well as reacting directly with oxidants.[45] 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.[50] In some organisms glutathione is replaced by other thiols, such as by mycothiol in the Actinomycetes, or by trypanothione in the Kinetoplastids.[52][53]
Melatonin
Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[54] 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.[55]
Tocopherols and tocotrienols (vitamin E)
Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols, which are fat-soluble vitamins with antioxidant properties.[56][57] Of these, α-tocopherol has been most studied as it has the highest bioavailability, with the body preferentially absorbing and metabolising this form.[58]
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.[56][59] 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.[60] 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[61]. 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,[62][63] 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.[64][65] 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,[58] and tocotrienols may be important in protecting neurons from damage.[66]
Pro-oxidant activities
Further information: Pro-oxidant
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,[67] however, it will also reduce metal ions that generate free radicals through the Fenton reaction.[68][69]
- 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, for example, appears to have a mostly antioxidant action in the body.[68][70] However, less data is available for other dietary antioxidants, such as vitamin E,[71] or the polyphenols.[72]
Enzyme systems
Overview
As with the chemical antioxidants, cells are protected against oxidative stress by an interacting network of antioxidant enzymes.[1][9] 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.[73]
Superoxide dismutase, catalase and peroxiredoxins
Superoxide dismutases (SODs) are a class of closely related enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide.[74][75] SOD enzymes are present in almost all aerobic cells and in extracellular fluids.[76] 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.[75] There also exists a third form of SOD in extracellular fluids, which contains copper and zinc in its active sites.[77] The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth.[78] 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).[73][79] 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.[80]
Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor.[81][82] This protein is localized to peroxisomes in most eukaryotic cells.[83] 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.[84] 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.[85][86]
Peroxiredoxins are peroxidases that catalyze the reduction of hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite.[88] They are divided into three classes: typical 2-cysteine peroxiredoxins; atypical 2-cysteine peroxiredoxins; and 1-cysteine peroxiredoxins.[89] 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.[90] Over-oxidation of this cysteine residue in peroxiredoxins inactivates these enzymes, but this can be reversed by the action of sulfiredoxin.[91] 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.[92][93][94]
Thioredoxin and glutathione systems
The thioredoxin system contains the 12-kDa protein thioredoxin and its companion thioredoxin reductase.[95] Proteins related to thioredoxin are present in all sequenced organisms, with plants such as Arabidopsis thaliana having a particularly great diversity of isoforms.[96] 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.[97] After being oxidized, the active thioredoxin is regenerated by the action of thioredoxin reductase, using NADPH as an electron donor.[98]
The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases and glutathione S-transferases.[50] This system is found in animals, plants and microorganisms.[50][99] 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.[100] 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,[101] but they are hypersensitive to induced oxidative stress.[102] In addition, the glutathione S-transferases show high activity with lipid peroxides.[103] These enzymes are at particularly high levels in the liver and also serve in detoxification metabolism.[104]
Oxidative stress in disease
Further information: Pathology, Free-radical theory of aging
Oxidative stress is thought to contribute to the development of a wide range of diseases including Alzheimer's disease,[105][106] Parkinson's disease,[107] the pathologies caused by diabetes,[108][109] rheumatoid arthritis,[110] and neurodegeneration in motor neurone diseases.[111] In many of these cases, it is unclear if oxidants trigger the disease, or if they are produced as a secondary consequence of the disease and from general tissue damage;[12] 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.[112][113]
A low calorie diet extends median and maximum lifespan in many animals. This effect may involve a reduction in oxidative stress.[114] While there is some evidence to support the role of oxidative stress in aging in model organisms such as Drosophila melanogaster and Caenorhabditis elegans,[115][116] the evidence in mammals is less clear.[117][118][119] Diets high 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 may be unrelated to their antioxidant contents.[120][121] 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, so it may be these other non-antioxidant effects that are the real reason they are important in human nutrition.[64][122]
Health effects
Disease treatment
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.[123] Consequently, antioxidants are commonly used as medications to treat various forms of brain injury. Here, superoxide dismutase mimetics,[124] sodium thiopental and propofol are used to treat reperfusion injury and traumatic brain injury,[125] while the experimental drug NXY-059[126][127] and ebselen[128] 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,[129][130] and as a way to prevent noise-induced hearing loss.[131]
Disease prevention
Antioxidants can cancel out the cell-damaging effects of free radicals.[1] Furthermore, people who eat fruits and vegetables, which happen to be good sources of antioxidants, have a lower risk of heart disease and some neurological diseases,[132] and there is evidence that some types of vegetables, and fruits in general, protect against a number of cancers.[133] These observations suggested the idea that antioxidants might help prevent these conditions. However, this hypothesis has now been tested in many clinical trials and does not seem to be true, since antioxidant supplements have no clear effect on the risk of chronic diseases such as cancer and heart disease.[132][134] This suggests that 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.[135][136] However, there is some evidence that antioxidants might help prevent other diseases such as macular degeneration,[137] suppressed immunity due to poor nutrition,[138] and neurodegeneration.[139]
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.[140] 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.[141] Further studies have also been negative.[142][143] 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.[144] 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.[145][146]
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.[147] 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, in a post-hoc analysis they found a 31% reduction in the risk of cancer in men, but not women.
Many nutraceutical and health food companies sell formulations of antioxidants as dietary supplements and these are widely used in industrialized countries.[148] These supplements may include specific antioxidant chemicals, like resveratrol (from grape seeds or knotweed roots),[149] 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 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 these antioxidant supplements are beneficial or harmful, and if they are actually beneficial, which antioxidant(s) are needed and in what amounts.[132][134][150] Indeed, some authors argue that the hypothesis that antioxidants could prevent chronic diseases has now been disproven and that the idea was misguided from the beginning.[151]
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.[152] However, the suggestion that increased life expectancy comes from increased oxidative stress conflicts with results seen in the yeast Saccharomyces cerevisiae,[153] and the situation in mammals is even less clear.[117][154][155] Nevertheless, antioxidant supplements do not appear to increase life expectancy in humans.[156]
Physical exercise
During exercise, oxygen consumption can increase by a factor of more than 10.[157] 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.[158] Antioxidant supplements may also prevent any of the health gains that normally come from exercise, such as increased insulin sensitivity.[159]
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.[160] 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.[161]
However, no benefits for physical performance to athletes are seen with vitamin E supplementation.[162] 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.[163] 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.[164][165] However, other studies found no such effects, and some research suggests that supplementation with amounts as high as 1000 mg inhibits recovery.[166]
Adverse effects
Further information: Micronutrients
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.[167] Notable examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets.[168] 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.[169]
| Foods | Reducing acid present |
|---|---|
| Cocoa and chocolate, spinach, turnip and rhubarb.[170] | Oxalic acid |
| Whole grains, maize, legumes.[171] | Phytic acid |
| Tea, beans, cabbage.[170][172] | 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.[173] 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.[174] 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.[175] Subsequent studies confirmed these adverse effects.[176]
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.[177] 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. However, 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.[178] 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.[179] These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality,[180] and that antioxidant supplements increased the risk of colon cancer.[181] 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.[147][182][183][184] 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.[132][134][177]
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.[185] 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 could decrease the effectiveness of radiotherapy and chemotherapy.[186][187] However, the evidence is mixed, and some reviews indicate that antioxidants could reduce side effects or increase survival times.[188][189]
Measurement and levels in food
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.[190][191] Other measurement tests include the Folin-Ciocalteu reagent, and the Trolox equivalent antioxidant capacity assay.[192] The CAP-e assay measures antioxidants that are available to enter and protect live cells.[193]
Antioxidants are found in varying amounts in foods such as vegetables, fruits, grain cereals, eggs, meat, legumes and nuts. Some antioxidants such as lycopene and ascorbic acid can be destroyed by long-term storage or prolonged cooking.[194][195] Other antioxidant compounds are more stable, such as the polyphenolic antioxidants in foods such as whole-wheat cereals and tea.[196][197] 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.[198] In general, processed foods contain fewer antioxidants than fresh and uncooked foods, since the preparation processes may expose the food to oxygen.[199]
| Antioxidant compounds | Foods containing high levels of these antioxidants[172][200][201] |
|---|---|
| Vitamin C (ascorbic acid) | Fruits and vegetables |
| Vitamin E (tocopherols, tocotrienols) | Vegetable oils |
| Polyphenolic antioxidants (resveratrol, flavonoids) | Tea, coffee, soy, fruit, olive oil, chocolate, cinnamon, oregano and red wine |
| Carotenoids (lycopene, carotenes, lutein) | Fruit, vegetables and eggs.[202] |
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.[42] 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.[203][204] Although large amounts of sulfur-containing amino acids such as acetylcysteine can increase glutathione,[205] no evidence exists that eating high levels of these glutathione precursors is beneficial for healthy adults.[206] 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.[205][207]
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.[151] 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.[208][151]
Uses in technology
Food preservatives
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.[209] 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.[210] 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).[211][212]
The most common molecules attacked by oxidation are unsaturated fats; oxidation causes them to turn rancid.[213] 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.[214] Antioxidant preservatives are also added to fat-based cosmetics such as lipstick and moisturizers to prevent rancidity.
Industrial uses
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.[215]
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.[216] Polymers containing double bonds in their main chains are especially susceptible to oxidation and ozonolysis. Solid polymer products start to crack on exposed surfaces as the material degrades and the chains unzip. 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. Ozone cracking is especially damaging to elastomers such as natural rubber, polybutadiene and other double-bonded rubbers. They can be protected by antiozonants. 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 suceptible 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.
| Fuel additive | Components[217] | Applications[217] |
|---|---|---|
| AO-22 | N,N'-di-2-butyl-1,4-phenylenediamine | Turbine oils, transformer oils, hydraulic fluids, waxes, and greases |
| AO-24 | N,N'-di-2-butyl-1,4-phenylenediamine | Low-temperature oils |
| AO-29 | 2,6-di-tert-butyl-4-methylphenol | Turbine oils, transformer oils, hydraulic fluids, waxes, greases, and gasolines |
| AO-30 | 2,4-dimethyl-6-tert-butylphenol | Jet fuels and gasolines, including aviation gasolines |
| AO-31 | 2,4-dimethyl-6-tert-butylphenol | Jet fuels and gasolines, including aviation gasolines |
| AO-32 | 2,4-dimethyl-6-tert-butylphenol and 2,6-di-tert-butyl-4-methylphenol | Jet fuels and gasolines, including aviation gasolines |
| AO-37 | 2,6-di-tert-butylphenol | Jet fuels and gasolines, widely approved for aviation fuels |
See also
- Forensic engineering
- Free radical theory
- Nootropics
- Nutrition
- Phytochemical
- Mitohormesis
- Polymer degradation
- Antiozonant
- Evolution of dietary antioxidants
Further reading
- Nick Lane Oxygen: The Molecule That Made the World (Oxford University Press, 2003) ISBN 0-198-60783-0
- Barry Halliwell and John M.C. Gutteridge Free Radicals in Biology and Medicine(Oxford University Press, 2007) ISBN 0-198-56869-X
- Jan Pokorny, Nelly Yanishlieva and Michael H. Gordon Antioxidants in Food: Practical Applications (CRC Press Inc, 2001) ISBN 0-849-31222-1
References
- ^ a b c d e f g Sies H (1997). "Oxidative stress: oxidants and antioxidants" (PDF). Exp Physiol 82 (2): 291–5. PMID 9129943. http://ep.physoc.org/cgi/reprint/82/2/291.pdf.
- ^ Bjelakovic G, et al. (2007). "Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis". JAMA 297 (8): 842–57. doi:. PMID 17327526.
- ^ Matill HA (1947). Antioxidants. Annu Rev Biochem 16: 177–192.
- ^ German J (1999). "Food processing and lipid oxidation". Adv Exp Med Biol 459: 23–50. PMID 10335367.
- ^ Jacob R (1996). "Three eras of vitamin C discovery". Subcell Biochem 25: 1–16. PMID 8821966.
- ^ Knight J (1998). "Free radicals: their history and current status in aging and disease". Ann Clin Lab Sci 28 (6): 331–46. PMID 9846200.
- ^ Moreau and Dufraisse, (1922) Comptes Rendus des Séances et Mémoires de la Société de Biologie, 86, 321.
- ^ Wolf G (01 Mar 2005). "The discovery of the antioxidant function of vitamin E: the contribution of Henry A. Mattill". J Nutr 135 (3): 363–6. PMID 15735064. http://jn.nutrition.org/cgi/content/full/135/3/363.
- ^ a b c Davies K (1995). "Oxidative stress: the paradox of aerobic life". Biochem Soc Symp 61: 1–31. PMID 8660387.
- ^ a b c d Vertuani S, Angusti A, Manfredini S (2004). "The antioxidants and pro-antioxidants network: an overview". Curr Pharm Des 10 (14): 1677–94. doi:. PMID 15134565.
- ^ Rhee SG (June 2006). "Cell signaling. H2O2, a necessary evil for cell signaling". Science (journal) 312 (5782): 1882–3. doi:. PMID 16809515.
- ^ a b Valko M, Leibfritz D, Moncol J, Cronin M, Mazur M, Telser J (2007). "Free radicals and antioxidants in normal physiological functions and human disease". Int J Biochem Cell Biol 39 (1): 44–84. doi:. PMID 16978905.
- ^ Stohs S, Bagchi D (1995). "Oxidative mechanisms in the toxicity of metal ions". Free Radic Biol Med 18 (2): 321–36. doi:. PMID 7744317.
- ^ Nakabeppu Y, Sakumi K, Sakamoto K, Tsuchimoto D, Tsuzuki T, Nakatsu Y (2006). "Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids". Biol Chem 387 (4): 373–9. doi:. PMID 16606334.
- ^ Valko M, Izakovic M, Mazur M, Rhodes C, Telser J (2004). "Role of oxygen radicals in DNA damage and cancer incidence". Mol Cell Biochem 266 (1–2): 37–56. doi:. PMID 15646026.
- ^ Stadtman E (1992). "Protein oxidation and aging". Science 257 (5074): 1220–4. doi:. PMID 1355616.
- ^ Raha S, Robinson B (2000). "Mitochondria, oxygen free radicals, disease and aging". Trends Biochem Sci 25 (10): 502–8. doi:. PMID 11050436.
- ^ Lenaz G (2001). "The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology". IUBMB Life 52 (3–5): 159–64. doi:. PMID 11798028.
- ^ Finkel T, Holbrook NJ (2000). "Oxidants, oxidative stress and the biology of aging". Nature 408 (6809): 239–47. doi:. PMID 11089981.
- ^ Hirst J, King MS, Pryde KR (October 2008). "The production of reactive oxygen species by complex I". Biochem. Soc. Trans. 36 (Pt 5): 976–80. doi:. PMID 18793173.
- ^ Seaver LC, Imlay JA (November 2004). "Are respiratory enzymes the primary sources of intracellular hydrogen peroxide?". J. Biol. Chem. 279 (47): 48742–50. doi:. PMID 15361522. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15361522.
- ^ Imlay JA (2003). "Pathways of oxidative damage". Annu. Rev. Microbiol. 57: 395–418. doi:. PMID 14527285.
- ^ Demmig-Adams B, Adams WW (December 2002). "Antioxidants in photosynthesis and human nutrition". Science (journal) 298 (5601): 2149–53. doi:. PMID 12481128.
- ^ Krieger-Liszkay A (2005). "Singlet oxygen production in photosynthesis". J Exp Bot 56 (411): 337–46. doi:. PMID 15310815. http://jxb.oxfordjournals.org/cgi/content/full/56/411/337.
- ^ Szabó I, Bergantino E, Giacometti G (2005). "Light and oxygenic photosynthesis: energy dissipation as a protection mechanism against photo-oxidation". EMBO Rep 6 (7): 629–34. doi:. PMID 15995679.
- ^ Kerfeld CA (October 2004). "Water-soluble carotenoid proteins of cyanobacteria". Arch. Biochem. Biophys. 430 (1): 2–9. doi:. PMID 15325905.
- ^ Miller RA, Britigan BE (January 1997). "Role of oxidants in microbial pathophysiology". Clin. Microbiol. Rev. 10 (1): 1–18. PMID 8993856. PMC: 172912. http://cmr.asm.org/cgi/pmidlookup?view=long&pmid=8993856.
- ^ Chaudière J, Ferrari-Iliou R (1999). "Intracellular antioxidants: from chemical to biochemical mechanisms". Food Chem Toxicol 37 (9–10): 949 – 62. doi:. PMID 10541450.
- ^ Sies H (1993). "Strategies of antioxidant defense". Eur J Biochem 215 (2): 213 – 9. doi:. PMID 7688300.
- ^ Imlay J (2003). "Pathways of oxidative damage". Annu Rev Microbiol 57: 395–418. doi:. PMID 14527285.
- ^ Ames B, Cathcart R, Schwiers E, Hochstein P (1981). "Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis". Proc Natl Acad Sci USA 78 (11): 6858–62. doi:. PMID 6947260.
- ^ Khaw K, Woodhouse P (1995). "Interrelation of vitamin C, infection, haemostatic factors, and cardiovascular disease". BMJ 310 (6994): 1559 – 63. PMID 7787643. http://www.bmj.com/cgi/content/full/310/6994/1559.
- ^ a b c d Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi E (2001). "Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols". Arch Biochem Biophys 388 (2): 261 – 6. doi:. PMID 11368163.
- ^ Morrison JA, Jacobsen DW, Sprecher DL, Robinson K, Khoury P, Daniels SR (30 November 1999). "Serum glutathione in adolescent males predicts parental coronary heart disease". Circulation 100 (22): 2244–7. PMID 10577998. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=10577998.
- ^ Teichert J, Preiss R (1992). "HPLC-methods for determination of lipoic acid and its reduced form in human plasma". Int J Clin Pharmacol Ther Toxicol 30 (11): 511 – 2. PMID 1490813.
- ^ Akiba S, Matsugo S, Packer L, Konishi T (1998). "Assay of protein-bound lipoic acid in tissues by a new enzymatic method". Anal Biochem 258 (2): 299 – 304. doi:. PMID 9570844.
- ^ Glantzounis G, Tsimoyiannis E, Kappas A, Galaris D (2005). "Uric acid and oxidative stress". Curr Pharm Des 11 (32): 4145 – 51. doi:. PMID 16375736.
- ^ El-Sohemy A, Baylin A, Kabagambe E, Ascherio A, Spiegelman D, Campos H (2002). "Individual carotenoid concentrations in adipose tissue and plasma as biomarkers of dietary intake". Am J Clin Nutr 76 (1): 172 – 9. PMID 12081831.
- ^ a b Sowell A, Huff D, Yeager P, Caudill S, Gunter E (1994). "Retinol, alpha-tocopherol, lutein/zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, trans-beta-carotene, and four retinyl esters in serum determined simultaneously by reversed-phase HPLC with multiwavelength detection". Clin Chem 40 (3): 411 – 6. PMID 8131277. http://www.clinchem.org/cgi/reprint/40/3/411.pdf?ijkey=12d7f1fb0a06f27c93b282ad4ea3435c0fb78f7e.
- ^ Stahl W, Schwarz W, Sundquist A, Sies H (1992). "cis-trans isomers of lycopene and beta-carotene in human serum and tissues". Arch Biochem Biophys 294 (1): 173 – 7. doi:. PMID 1550343.
- ^ Zita C, Overvad K, Mortensen S, Sindberg C, Moesgaard S, Hunter D (2003). "Serum coenzyme Q10 concentrations in healthy men supplemented with 30 mg or 100 mg coenzyme Q10 for two months in a randomised controlled study". Biofactors 18 (1 – 4): 185 – 93. doi:. PMID 14695934.
- ^ a b Turunen M, Olsson J, Dallner G (2004). "Metabolism and function of coenzyme Q". Biochim Biophys Acta 1660 (1 – 2): 171 – 99. doi:. PMID 14757233.
- ^ Smirnoff N (2001). "L-ascorbic acid biosynthesis". Vitam Horm 61: 241 – 66. doi:. PMID 11153268.
- ^ Linster CL, Van Schaftingen E (2007). "Vitamin C. Biosynthesis, recycling and degradation in mammals". Febs J. 274 (1): 1–22. doi:. PMID 17222174.
- ^ a b Meister A (1994). "Glutathione-ascorbic acid antioxidant system in animals". J Biol Chem 269 (13): 9397 – 400. PMID 8144521.
- ^ Wells W, Xu D, Yang Y, Rocque P (15 Sep 1990). "Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity". J Biol Chem 265 (26): 15361 – 4. PMID 2394726. http://www.jbc.org/cgi/reprint/265/26/15361.
- ^ Padayatty S, Katz A, Wang Y, Eck P, Kwon O, Lee J, Chen S, Corpe C, Dutta A, Dutta S, Levine M (01 Feb 2003). "Vitamin C as an antioxidant: evaluation of its role in disease prevention". J Am Coll Nutr 22 (1): 18 – 35. PMID 12569111. http://www.jacn.org/cgi/content/full/22/1/18.
- ^ Shigeoka S, Ishikawa T, Tamoi M, Miyagawa Y, Takeda T, Yabuta Y, Yoshimura K (2002). "Regulation and function of ascorbate peroxidase isoenzymes". J Exp Bot 53 (372): 1305 – 19. doi:. PMID 11997377. http://jxb.oxfordjournals.org/cgi/content/full/53/372/1305.
- ^ Smirnoff N, Wheeler GL (2000). "Ascorbic acid in plants: biosynthesis and function". Crit. Rev. Biochem. Mol. Biol. 35 (4): 291–314. doi:. PMID 11005203.
- ^ a b c d Meister A, Anderson M (1983). "Glutathione". Annu Rev Biochem 52: 711 – 60. doi:. PMID 6137189.
- ^ Meister A (1988). "Glutathione metabolism and its selective modification" (PDF). J Biol Chem 263 (33): 17205 – 8. doi:. PMID 3053703. http://www.jbc.org/cgi/reprint/263/33/17205.pdf.
- ^ Fahey RC (2001). "Novel thiols of prokaryotes". Annu. Rev. Microbiol. 55: 333–56. doi:. PMID 11544359.
- ^ Fairlamb AH, Cerami A (1992). "Metabolism and functions of trypanothione in the Kinetoplastida". Annu. Rev. Microbiol. 46: 695–729. doi:. PMID 1444271.
- ^ Reiter RJ, Carneiro RC, Oh CS (1997). "Melatonin in relation to cellular antioxidative defense mechanisms". Horm. Metab. Res. 29 (8): 363–72. doi:. PMID 9288572.
- ^ Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR (2000). "Significance of melatonin in antioxidative defense system: reactions and products". Biological signals and receptors 9 (3–4): 137–59. doi:. PMID 10899700.
- ^ a b Herrera E, Barbas C (2001). "Vitamin E: action, metabolism and perspectives". J Physiol Biochem 57 (2): 43 – 56. PMID 11579997.
- ^ Packer L, Weber SU, Rimbach G (01 Feb 2001). "Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling". J. Nutr. 131 (2): 369S–73S. PMID 11160563. http://jn.nutrition.org/cgi/content/full/131/2/369S.
- ^ a b Brigelius-Flohé R, Traber M (01 Jul 1999). "Vitamin E: function and metabolism". Faseb J 13 (10): 1145 – 55. PMID 10385606. http://www.fasebj.org/cgi/content/full/13/10/1145.
- ^ Traber MG, Atkinson J (2007). "Vitamin E, antioxidant and nothing more". Free Radic. Biol. Med. 43 (1): 4–15. doi:. PMID 17561088.
- ^ Wang X, Quinn P (1999). "Vitamin E and its function in membranes". Prog Lipid Res 38 (4): 309 – 36. doi:. PMID 10793887.
- ^ Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (September 2008). "Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death". Cell Metab. 8 (3): 237–48. doi:. PMID 18762024.
- ^ Brigelius-Flohé R, Davies KJ (2007). "Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food? Comments on the two accompanying papers: "Molecular mechanism of alpha-tocopherol action" by A. Azzi and "Vitamin E, antioxidant and nothing more" by M. Traber and J. Atkinson". Free Radic. Biol. Med. 43 (1): 2–3. PMID 17561087.
- ^ Atkinson J, Epand RF, Epand RM (2007). "Tocopherols and tocotrienols in membranes: A critical review". Free Radic. Biol. Med. 44 (5): 739–764. doi:. PMID 18160049.
- ^ a b Azzi A (2007). "Molecular mechanism of alpha-tocopherol action". Free Radic. Biol. Med. 43 (1): 16–21. doi:. PMID 17561089.
- ^ Zingg JM, Azzi A (2004). "Non-antioxidant activities of vitamin E". Curr. Med. Chem. 11 (9): 1113–33. PMID 15134510.
- ^ Sen C, Khanna S, Roy S (2006). "Tocotrienols: Vitamin E beyond tocopherols". Life Sci 78 (18): 2088–98. doi:. PMID 16458936.
- ^ 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:. PMID 16036346.
- ^ a b Carr A, Frei B (01 Jun 1999). "Does vitamin C act as a pro-oxidant under physiological conditions?". Faseb J. 13 (9): 1007–24. PMID 10336883. http://www.fasebj.org/cgi/content/full/13/9/1007.
- ^ Stohs SJ, Bagchi D (1995). "Oxidative mechanisms in the toxicity of metal ions". Free Radic. Biol. Med. 18 (2): 321–36. doi:. PMID 7744317.
- ^ Valko M, Morris H, Cronin MT (2005). "Metals, toxicity and oxidative stress". Curr. Med. Chem. 12 (10): 1161–208. doi:. PMID 15892631.
- ^ Schneider C (2005). "Chemistry and biology of vitamin E". Mol Nutr Food Res 49 (1): 7–30. doi:. PMID 15580660.
- ^ Halliwell, B. (2008). "Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?". Archives of Biochemistry and Biophysics 476 (2): 107–112. doi:.
- ^ a b Ho YS, Magnenat JL, Gargano M, Cao J (October 1998). "The nature of antioxidant defense mechanisms: a lesson from transgenic studies". Environ. Health Perspect. 106 (Suppl 5): 1219–28. doi:. PMID 9788901.
- ^ 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 Med 33 (3): 337–49. doi:. PMID 12126755.
- ^ a b Bannister J, Bannister W, Rotilio G (1987). "Aspects of the structure, function, and applications of superoxide dismutase". CRC Crit Rev Biochem 22 (2): 111–80. doi:. PMID 3315461.
- ^ Johnson F, Giulivi C (2005). "Superoxide dismutases and their impact upon human health". Mol Aspects Med 26 (4–5): 340–52. doi:. PMID 16099495.
- ^ Nozik-Grayck E, Suliman H, Piantadosi C (2005). "Extracellular superoxide dismutase". Int J Biochem Cell Biol 37 (12): 2466–71. doi:. PMID 16087389.
- ^ 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 Genet 18 (2): 159–63. doi:. PMID 9462746.
- ^ 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 Genet 13 (1): 43–7. doi:. PMID 8673102.
- ^ Van Camp W, Inzé D, Van Montagu M (1997). "The regulation and function of tobacco superoxide dismutases". Free Radic Biol Med 23 (3): 515–20. doi:. PMID 9214590.
- ^ Chelikani P, Fita I, Loewen P (2004). "Diversity of structures and properties among catalases". Cell Mol Life Sci 61 (2): 192–208. doi:. PMID 14745498.
- ^ Zámocký M, Koller F (1999). "Understanding the structure and function of catalases: clues from molecular evolution and in vitro mutagenesis". Prog Biophys Mol Biol 72 (1): 19–66. doi:. PMID 10446501.
- ^ del Río L, Sandalio L, Palma J, Bueno P, Corpas F (1992). "Metabolism of oxygen radicals in peroxisomes and cellular implications". Free Radic Biol Med 13 (5): 557–80. doi:. PMID 1334030.
- ^ Hiner A, Raven E, Thorneley R, García-Cánovas F, Rodríguez-López J (2002). "Mechanisms of compound I formation in heme peroxidases". J Inorg Biochem 91 (1): 27–34. doi:. PMID 12121759.
- ^ Mueller S, Riedel H, Stremmel W (15 Dec 1997). "Direct evidence for catalase as the predominant H2O2 -removing enzyme in human erythrocytes". Blood 90 (12): 4973–8. PMID 9389716. http://www.bloodjournal.org/cgi/content/full/90/12/4973.
- ^ Ogata M (1991). "Acatalasemia". Hum Genet 86 (4): 331–40. doi:. PMID 1999334.
- ^ Parsonage D, Youngblood D, Sarma G, Wood Z, Karplus P, Poole L (2005). "Analysis of the link between enzymatic activity and oligomeric state in AhpC, a bacterial peroxiredoxin". Biochemistry 44 (31): 10583–92. doi:. PMID 16060667. PDB 1YEX
- ^ Rhee S, Chae H, Kim K (2005). "Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling". Free Radic Biol Med 38 (12): 1543–52. doi:. PMID 15917183.
- ^ Wood Z, Schröder E, Robin Harris J, Poole L (2003). "Structure, mechanism and regulation of peroxiredoxins". Trends Biochem Sci 28 (1): 32–40. doi:. PMID 12517450.
- ^ 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". Biochemistry 38 (47): 15407–16. doi:. PMID 10569923.
- ^ Jönsson TJ, Lowther WT (2007). "The peroxiredoxin repair proteins". Sub-cellular biochemistry 44: 115–41. doi:. PMID 18084892.
- ^ 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". Nature 424 (6948): 561–5. doi:. PMID 12891360.
- ^ Lee T, Kim S, Yu S, Kim S, Park D, Moon H, Dho S, Kwon K, Kwon H, Han Y, Jeong S, Kang S, Shin H, Lee K, Rhee S, Yu D (2003). "Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice". Blood 101 (12): 5033–8. doi:. PMID 12586629. http://www.bloodjournal.org/cgi/content/full/101/12/5033.
- ^ 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 Bot 57 (8): 1697–709. doi:. PMID 16606633.
- ^ Nordberg J, Arner ES (2001). "Reactive oxygen species, antioxidants, and the mammalian thioredoxin system". Free Radic Biol Med 31 (11): 1287–312. doi:. PMID 11728801.
- ^ Vieira Dos Santos C, Rey P (2006). "Plant thioredoxins are key actors in the oxidative stress response". Trends Plant Sci 11 (7): 329–34. doi:. PMID 16782394.
- ^ Arnér E, Holmgren A (2000). "Physiological functions of thioredoxin and thioredoxin reductase". Eur J Biochem 267 (20): 6102–9. doi:. PMID 11012661. http://www.blackwell-synergy.com/doi/full/10.1046/j.1432-1327.2000.01701.x.
- ^ Mustacich D, Powis G (2000). "Thioredoxin reductase". Biochem J 346 (Pt 1): 1–8. doi:. PMID 10657232.
- ^ Creissen G, Broadbent P, Stevens R, Wellburn A, Mullineaux P (1996). "Manipulation of glutathione metabolism in transgenic plants". Biochem Soc Trans 24 (2): 465–9. PMID 8736785.
- ^ Brigelius-Flohé R (1999). "Tissue-specific functions of individual glutathione peroxidases". Free Radic Biol Med 27 (9–10): 951–65. doi:. PMID 10569628.
- ^ 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 Chem 272 (26): 16644–51. doi:. PMID 9195979. http://www.jbc.org/cgi/content/full/272/26/16644.
- ^ 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 Chem 273 (35): 22528–36. doi:. PMID 9712879. http://www.jbc.org/cgi/content/full/273/35/22528.
- ^ 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 Signal 6 (2): 289–300. doi:. PMID 15025930.
- ^ Hayes J, Flanagan J, Jowsey I (2005). "Glutathione transferases". Annu Rev Pharmacol Toxicol 45: 51–88. doi:. PMID 15822171.
- ^ Christen Y (01 Feb 2000). "Oxidative stress and Alzheimer disease". Am J Clin Nutr 71 (2): 621S–629S. PMID 10681270. http://www.ajcn.org/cgi/content/full/71/2/621s.
- ^ Nunomura A, Castellani R, Zhu X, Moreira P, Perry G, Smith M (2006). "Involvement of oxidative stress in Alzheimer disease". J Neuropathol Exp Neurol 65 (7): 631–41. doi:. PMID 16825950.
- ^ Wood-Kaczmar A, Gandhi S, Wood N (2006). "Understanding the molecular causes of Parkinson's disease". Trends Mol Med 12 (11): 521–8. doi:. PMID 17027339.
- ^ Davì G, Falco A, Patrono C (2005). "Lipid peroxidation in diabetes mellitus". Antioxid Redox Signal 7 (1–2): 256–68. doi:. PMID 15650413.
- ^ Giugliano D, Ceriello A, Paolisso G (1996). "Oxidative stress and diabetic vascular complications". Diabetes Care 19 (3): 257–67. doi:. PMID 8742574.
- ^ Hitchon C, El-Gabalawy H (2004). "Oxidation in rheumatoid arthritis". Arthritis Res Ther 6 (6): 265–78. doi:. PMID 15535839.
- ^ Cookson M, Shaw P (1999). "Oxidative stress and motor neurone disease". Brain Pathol 9 (1): 165–86. PMID 9989458.
- ^ Van Gaal L, Mertens I, De Block C (2006). "Mechanisms linking obesity with cardiovascular disease". Nature 444 (7121): 875–80. doi:. PMID 17167476.
- ^ Aviram M (2000). "Review of human studies on oxidative damage and antioxidant protection related to cardiovascular diseases". Free Radic Res 33 Suppl: S85–97. PMID 11191279.
- ^ G. López-Lluch, N. Hunt, B. Jones, M. Zhu, H. Jamieson, S. Hilmer, M. V. Cascajo, J. Allard, D. K. Ingram, P. Navas, and R. de Cabo (2006). "Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency". Proc Natl Acad Sci USA 103 (6): 1768 – 1773. doi:. PMID 16446459.
- ^ Larsen P (1993). "Aging and resistance to oxidative damage in Caenorhabditis elegans". Proc Natl Acad Sci USA 90 (19): 8905–9. doi:. PMID 8415630.
- ^ Helfand S, Rogina B (2003). "Genetics of aging in the fruit fly, Drosophila melanogaster". Annu Rev Genet 37: 329–48. doi:. PMID 14616064.
- ^ a b Sohal R, Mockett R, Orr W (2002). "Mechanisms of aging: an appraisal of the oxidative stress hypothesis". Free Radic Biol Med 33 (5): 575–86. doi:. PMID 12208343.
- ^ Sohal R (2002). "Role of oxidative stress and protein oxidation in the aging process". Free Radic Biol Med 33 (1): 37–44. doi:. PMID 12086680.
- ^ Rattan S (2006). "Theories of biological aging: genes, proteins, and free radicals". Free Radic Res 40 (12): 1230–8. doi:. PMID 17090411.
- ^ Thomas D (2004). "Vitamins in health and aging". Clin Geriatr Med 20 (2): 259–74. doi:. PMID 15182881.
- ^ Ward J (1998). "Should antioxidant vitamins be routinely recommended for older people?". Drugs Aging 12 (3): 169–75. doi:. PMID 9534018.
- ^ Aggarwal BB, Shishodia S (2006). "Molecular targets of dietary agents for prevention and therapy of cancer". Biochem. Pharmacol. 71 (10): 1397–421. doi:. PMID 16563357.
- ^ Reiter R (1995). "Oxidative processes and antioxidative defense mechanisms in the aging brain" (PDF). Faseb J 9 (7): 526–33. PMID 7737461. http://www.fasebj.org/cgi/reprint/9/7/526.pdf.
- ^ Warner D, Sheng H, Batinić-Haberle I (2004). "Oxidants, antioxidants and the ischemic brain". J Exp Biol 207 (Pt 18): 3221–31. doi:. PMID 15299043. http://jeb.biologists.org/cgi/content/full/207/18/3221.
- ^ Wilson J, Gelb A (2002). "Free radicals, antioxidants, and neurologic injury: possible relationship to cerebral protection by anesthetics". J Neurosurg Anesthesiol 14 (1): 66–79. doi:. PMID 11773828.
- ^ 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". Stroke 37 (12): 2970–8. doi:. PMID 17068304.
- ^ 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 Med 354 (6): 588–600. doi:. PMID 16467546.
- ^ Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H (01 Jan 1998). "Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group". Stroke 29 (1): 12–7. PMID 9445321. http://stroke.ahajournals.org/cgi/content/full/29/1/12.
- ^ 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 Disord 2 (2): 95–107. doi:. PMID 12769802.
- ^ Rao A, Balachandran B (2002). "Role of oxidative stress and antioxidants in neurodegenerative diseases". Nutr Neurosci 5 (5): 291–309. doi:. PMID 12385592.
- ^ Kopke RD, Jackson RL, Coleman JK, Liu J, Bielefeld EC, Balough BJ (2007). "NAC for noise: from the bench top to the clinic". Hear. Res. 226 (1-2): 114–25. doi:. PMID 17184943.
- ^ a b c d Stanner SA, Hughes J, Kelly CN, Buttriss J (2004). "A review of the epidemiological evidence for the 'antioxidant hypothesis'". Public Health Nutr 7 (3): 407–22. doi:. PMID 15153272.
- ^ Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. World Cancer Research Fund (2007). ISBN 978-0-9722522-2-5.
- ^ a b c Shenkin A (2006). "The key role of micronutrients". Clin Nutr 25 (1): 1–13. doi:. PMID 16376462.
- ^ Cherubini A, Vigna G, Zuliani G, Ruggiero C, Senin U, Fellin R (2005). "Role of antioxidants in atherosclerosis: epidemiological and clinical update". Curr Pharm Des 11 (16): 2017–32. doi:. PMID 15974956.
- ^ Lotito SB, Frei B (2006). "Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon?". Free Radic. Biol. Med. 41 (12): 1727–46. doi:. PMID 17157175.
- ^ Bartlett H, Eperjesi F (2003). "Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials". Ophthalmic Physiol Opt 23 (5): 383–99. doi:. PMID 12950886.
- ^ Wintergerst E, Maggini S, Hornig D (2006). "Immune-enhancing role of vitamin C and zinc and effect on clinical conditions". Ann Nutr Metab 50 (2): 85–94. doi:. PMID 16373990.
- ^ Wang J, Wen L, Huang Y, Chen Y, Ku M (2006). "Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation". Curr Pharm Des 12 (27): 3521–33. doi:. PMID 17017945.
- ^ 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 Med 328 (20): 1450–6. doi:. PMID 8479464.
- ^ 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". Lancet 361 (9374): 2017–23. doi:. PMID 12814711.
- ^ Sesso HD, Buring JE, Christen WG, et al. (November 2008). "Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial". JAMA 300 (18): 2123–33. doi:. PMID 18997197. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=18997197.
- ^ Lee IM, Cook NR, Gaziano JM, et al. (July 2005). "Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial". JAMA 294 (1): 56–65. doi:. PMID 15998891. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=15998891.
- ^ Roberts LJ, Oates JA, Linton MF, et al. (2007). "The relationship between dose of vitamin E and suppression of oxidative stress in humans". Free Radic. Biol. Med. 43 (10): 1388–93. doi:. PMID 17936185.
- ^ 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. PMID 17023716.
- ^ Cook NR, Albert CM, Gaziano JM, et al. (2007). "A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study". Arch. Intern. Med. 167 (15): 1610–8. doi:. PMID 17698683.
- ^ a b Hercberg 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 Med 164 (21): 2335–42. doi:. PMID 15557412.
- ^ Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano M (2004). "Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999–2000". Am J Epidemiol 160 (4): 339–49. doi:. PMID 15286019. http://aje.oxfordjournals.org/cgi/content/full/160/4/339.
- ^ Latruffe N, Delmas D, Jannin B, Cherkaoui Malki M, Passilly-Degrace P, Berlot JP (December 2002). "Molecular analysis on the chemopreventive properties of resveratrol, a plant polyphenol microcomponent". Int. J. Mol. Med. 10 (6): 755–60. PMID 12430003.
- ^ Woodside J, McCall D, McGartland C, Young I (2005). "Micronutrients: dietary intake v. supplement use". Proc Nutr Soc 64 (4): 543–53. doi:. PMID 16313697.
- ^ a b c Hail N, Cortes M, Drake EN, Spallholz JE (July 2008). "Cancer chemoprevention: a radical perspective". Free Radic. Biol. Med. 45 (2): 97–110. doi:. PMID 18454943.
- ^ 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:. PMID 17908557.
- ^ 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:. PMID 15383542.
- ^ Sohal R (2002). "Role of oxidative stress and protein oxidation in the aging process". Free Radic Biol Med 33 (1): 37–44. doi:. PMID 12086680.
- ^ Rattan S (2006). "Theories of biological aging: genes, proteins, and free radicals". Free Radic Res 40 (12): 1230–8. doi:. PMID 17090411.
- ^ Green GA (December 2008). "Review: antioxidant supplements do not reduce all-cause mortality in primary or secondary prevention". Evid Based Med 13 (6): 177. doi:. PMID 19043035.
- ^ Dekkers J, van Doornen L, Kemper H (1996). "The role of antioxidant vitamins and enzymes in the prevention of exercise-induced muscle damage". Sports Med 21 (3): 213–38. doi:. PMID 8776010.
- ^ Tiidus P (1998). "Radical species in inflammation and overtraining". Can J Physiol Pharmacol 76 (5): 533–8. doi:. PMID 9839079. http://article.pubs.nrc-cnrc.gc.ca/ppv/RPViewDoc?issn=0008-4212&volume=76&issue=5&startPage=533.
- ^ Ristow M, Zarse K, Oberbach A, et al. (May 2009). "Antioxidants prevent health-promoting effects of physical exercise in humans". Proc. Natl. Acad. Sci. U.S.A.. doi:. PMID 19433800.
- ^ Leeuwenburgh C, Fiebig R, Chandwaney R, Ji L (1994). "Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems". Am J Physiol 267 (2 Pt 2): R439–45. PMID 8067452. http://ajpregu.physiology.org/cgi/reprint/267/2/R439.
- ^ Leeuwenburgh C, Heinecke J (2001). "Oxidative stress and antioxidants in exercise". Curr Med Chem 8 (7): 829–38. PMID 11375753.
- ^ Takanami Y, Iwane H, Kawai Y, Shimomitsu T (2000). "Vitamin E supplementation and endurance exercise: are there benefits?". Sports Med 29 (2): 73–83. doi:. PMID 10701711.
- ^ Mastaloudis A, Traber M, Carstensen K, Widrick J (2006). "Antioxidants did not prevent muscle damage in response to an ultramarathon run". Med Sci Sports Exerc 38 (1): 72–80. doi:. PMID 16394956.
- ^ Peake J (2003). "Vitamin C: effects of exercise and requirements with training". Int J Sport Nutr Exerc Metab 13 (2): 125–51. PMID 12945825.
- ^ Jakeman P, Maxwell S (1993). "Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise". Eur J Appl Physiol Occup Physiol 67 (5): 426–30. doi:. PMID 8299614.
- ^ Close G, Ashton T, Cable T, Doran D, Holloway C, McArdle F, MacLaren D (2006). "Ascorbic acid supplementation does not attenuate post-exercise muscle soreness following muscle-damaging exercise but may delay the recovery process". Br J Nutr 95 (5): 976–81. doi:. PMID 16611389.
- ^ Hurrell R (01 Sep 2003). "Influence of vegetable protein sources on trace element and mineral bioavailability". J Nutr 133 (9): 2973S–7S. PMID 12949395. http://jn.nutrition.org/cgi/content/full/133/9/2973S.
- ^ Hunt J (01 Sep 2003). "Bioavailability of iron, zinc, and other trace minerals from vegetarian diets". Am J Clin Nutr 78 (3 Suppl): 633S–639S. PMID 12936958. http://www.ajcn.org/cgi/content/full/78/3/633S.