Welcome to the world of antioxidants. There is a reason why you are hearing much news about antioxidants on TV commercials or in health fitness magazines. Free radicals are any species that contain one or more unpaired electrons and will take an electron from fat, proteins, or DNA for its full complement. Normal metabolic processes, pollution, solar, and cosmic radiation and smoking all affect our bodies by forming highly reactive cells. Antioxidants are molecules that prevent free radicals from doing harm to our DNA, proteins, and cells by donating an electron.
The most popular and abundant antioxidant vitamins are ascorbic acid (vitamin C), tocopherol (vitamin E) and beta-carotene. Medical studies show that antioxidants can help prevent certain diseases such as arteriosclerosis which can be brought on by free radicals oxidizing the low-density lipoprotein (LDL) cholesterol damaging the artery lining. There are also studies being done to find out if antioxidants can help prevent damaging affects of visible light on the retina and the lens epithelium. Another benefit that antioxidant vitamins may have, but is not yet proven, is their role in the prevention of cancer by stopping the attack of hydroxyl radicals on purine and pyridines which can then lead to mutations. Since our bodies do not produce vitamins, it is necessary for people to get their intake from vegetables and fruits. Vegetable and citrus fruits are good sources of vitamin C. Carrots and dark green leafy vegetables are high in beta-carotene and nuts, wheatgerm, and green leafy vegetables are rich in vitamin E.
Structure of antioxidant vitamins:
Vitamin C consists of a lactone ring that has two hydroxyl groups on it, two chiral carbons and has a uniqueness because it does not contain a carboxyl group but is an acidic molecule.
Vitamin C is a water soluble antioxidant which means that it will be located in the extracellular areas of the body. Ascorbic acid has much polarity because of the numerous hydroxyl groups making it dissolve in water easily. This is advantageous because ascorbic acid will be converted from the body more readily. Thus, vitamin C is able to react with aqueous free radicals and reactive oxygen. According to the American Journal of Medicine, vitamin C is the first antioxidant that is used up in defense of damaging free radicals.
Looking at the structure of vitamin E, one can see that the molecule is very nonpolar, the only remnant of polarity is the hydroxyl group and oxygen contained in the six-carbon ring, but the benzene ring and the long nonpolar hydrocarbon chain makes it a nonpolar molecule. Because of the hydrophobic nature of vitamin E, it is located in biological membranes and lipoproteins. It is a chain-breaking antioxidant which means it will disrupt the radical chain reactions of lipid peroxidation.
Beta-carotene is like tocopherol because it is also a lipid-soluble antioxidant. Compared to tocopherol, beta-carotene acts as a weak antioxidant and is only present in a 1/20 concentration of alpha-tocohpherol, and will only be used up after all other antioxidant defenses have been used.
Beta-carotene consists of a long nonpolar chain and will therefore be located in cell membranes and lipoproteins. It's capable of radical trapping and is a radical scavenger.
FUNCTION/ROLE:
The word "antioxidant" comes from the Greek "anti," meaning "against," plus "oxys," referring to oxidation. So, antioxidants are substances that work against oxydation. In your body, certain oxygen molecules, called free radicals, are normally produced by your body's own metabolism. But too many free radicals can cause problems. Many factors can cause your body to produce more free radicals than are needed. These may include smoking, drinking alcohol, too much fat in your diet, too much sun, even too much exercise, and too many pollutants in the air you breathe. When your body produces too many free radicals, the "extra" free radicals prey on healthy molecules.
Electrons normally exist in pairs. But free radicals have an unpaired electron. So they "raid" other molecules in your body to get an electron to pair up with, leaving the raided molecule short an electron. This causes changes in molecules (oxidation) that can eventually lead to disease. Antioxidants prevent this process by releasing unpaired electrons to "neutralize" the harmful, excess free radicals (which then do not need to "raid" healthy molecules and cause oxidation).
Free radicals are simply extremely reactive molecules, created as a waste by-product by the body's metabolic processes. Free radicals are so destructive that they are now regarded as primary agents of degeneration and death in nearly all living things, and have been shown to be responsible for the initiation of heart disease, aging, cancer, and other degenerative diseases. What antioxidants do is simply neutralize the free radicals, reducing their ability to damage the cells.
As a part of their normal function, cells make toxic molecules called free radicals. A free radical is a damaged molecule -- one that is missing an electron. Because the free-radical molecule "wants" its full complement of electrons, it reacts with any molecule from which it can take an electron. (illustration). By taking an electron from certain key components in the cell, such as fat, protein or DNA molecules, free radicals damage cells. Antioxidants that occur naturally in your body, or are obtained from certain foods may block some of this damage by donating electrons to stabilize and neutralize the harmful effects of the free radicals.
Antioxidants can scavenge free radicals before they cause damage, or prevent oxidative damage from spreading out. The antioxidant defense systems in the human body are extensive and consist of multiple layers that protect at different sites and against different types of free radicals. An important part of the intracellular antioxidant defense systems are antioxidant enzymes such as superoxide dismutase (SOD), catalase, and peroxidases. The enzyme SOD dismutates two molecules of O2*- per reaction cycle, i.e., oxidizes one molecule of O2*- to O2 and, with the electron released during this oxidation process, reduces a second O2*- molecule to H2O2 ( 2O2*- + 2H+ O2 + H2O2). In addition to these antioxidant enzymes, there are several small molecule antioxidants that also play an important role in antioxidant defense systems, particularly in the extracellular space, where antioxidant enzymes are absent or present in small quantities only. The small molecule antioxidants can be separated into lipid-soluble and water-soluble antioxidants. The lipid-soluble antioxidants are localized to membranes and lipoproteins, whereas the water-soluble ones are present in extracellular and intracellular fluids.
Antioxidants, have been found to slow, block or reverse oxidative changes in body substances and cells. For example, Vitamin C (Ascorbic Acid) prevents the conversion of nitrates (from tobacco smoke, smog, bacon, lunch meats, & some vegetables) into cancer-causing substances. Vitamin E retards cellular aging due to oxidation. It also helps to block oxidation that converts LDL cholesterol from a form that stays in the blood to a form that can stick to and clog arteries (atherosclerotic plaque buildups). Beta carotene has been shown to reverse precanacerous changes in cells that line the mouth and cervix.
Natural and synthetic antioxidants are added to food to prevent undesirable deterioration. Foods preserved with antioxidants include vegetable oils, bread, and cheese. Antioxidants are also frequently applied to the packaging materials of cereals and nuts.
Basically, antioxidants have the ability to trap organic free radicals and/or deactivate excited oxygen molecules. Practically speaking, they play a sigificant role in the prevention of aging, atherosclerosis (heart disease), certain types of cancer, cataracts, inflammatory-immune injuries / auto-immune diseases (rheumatoid arthritis, lupus), ARDS (Adult Respiratory Distress Syndrome), AIDS (Acquired Immunodeficiency Syndrome), etc.
Vitamin E :
High in Vitamin C, also contain beta carotene :
High in beta carotene also contain Vitamin C :
As the name implies, antioxidants are naturally occurring or synthetic substances which inhibit chemical reactions with oxygen. These reactions include oxidation reactions that cause cell damage in humans and other animals, as well as the degradation of fatty foods. Oxidation reactions many times involve free radicals -- highly reactive compounds -- and antioxidants are the substances which scavenge oxygen free radicals before they can damage important cell molecules. Thus, the function of antioxidants is regulated essentially by the process of oxidation.
As mentioned above, antioxidants can be naturally occurring or synthetic. Naturally occurring antioxidants include retinoids (vitamin A) and tocopherols (vitamin E), found in some plants and animals; ascorbic acid (vitamin C), found in some fruits, especially citrus ones, and vegetables; and beta-carotene, found in deep orange and dark green vegetables, to name a few. All of these are also available as supplements. Some synthetic antioxidants include butylated hydoxytoluene (BHT), butylated hydroxyanisole (BHA), and propyl gallate. These two types of antioxidants have been manipulated to play significant roles in the production of cosmetics (especially those designed to prevent the aging of skin), plastics, rubber, and probably most importantly, to prevent diseases such as some cancers and heart disease.
Since there is such a wide variety of antioxidants, each having different functions, the focus of this discussion on the control of antioxidants will be narrowed down to the following: a general explanation of the formation of free radicals, the scavenging of free radicals by antioxidants, and finally what effect this has on the control of cancer in humans. A free radical is any atom or molecule which contains one or more unpaired electrons. The unpaired electrons alter the chemical reactivity of an atom or molecule, usually making it more reactive than the corresponding non-radical. The chemical reactivity of radicals varies from poor to high, depending on the radical. A free radical is denoted by a superscripted dot. Free radicals can be formed by pollution, solar and cosmetic radiation, smoking, toxins and for the purpose of this discussion, by metabolic processes in the body.
For example, electron transport chains (refer to Figure 1), oxidases (e.g., NADPH, amino acids, xanthine, etc.), redox cycling (quinones), and cytochrome P-450 can yield the superoxide oxygen radical (O2*-). [This occurs when an electron is added to an oxygen molecule]. Although this radical is a poorly reactive one, it can again react with hydrogen to form hydrogen peroxide (H2O2) + O2. These molecules can again react with hydrogen to yield O2, H2O, and the fearsomely - reactive radical, a hydroxyl radical (HO*) (Refer to Fig 2).
A hydroxyl radical is a fine example of one which can lead to DNA mutations, which in turn can lead to cancer. Hydroxyl radicals will react with anything they are next to; therefore, if one is next to DNA, it may attack the purine and pyrimidine bases and cause mutations. In other words, a free radical, "wanting" a full compliment of electrons, will take an electron from key components in the cell (e.g., DNA bases), thereby causing cell damage and eventually leading to disease. For example, a hydroxyl radical may react with guanine to yield 8-hydroxyguanine radical and other products which are associated with cancer incidence (Refer to Fig 3).
As a protective response, cellular enzymes such as superoxide dismutase (found in mitochondria and cytosol) convert the free radicals into hydrogen peroxide and then into water and harmless oxygen. Antioxidants such as vitamins C and E, or beta-carotene act as assistants to the cell's enzyme protectors. They donate one of their electrons to the free radical (Refer to Fig 4), thus attaching to it and preventing it from attacking normal tissues. In essence, the antioxidants stabilize and neutralize the harmful effects of the free radicals (Refer to Fig 5).
Finally, strong evidence exists to prove that vitamins E and C and beta-carotene play a significant role in the prevention of cancer; however, cautions on the intake of some supplements do exist. According to Dr. Lines Pauling, considered the foremost authority on Vitamin C, Vitamin C will decrease the risk of getting most cancers by 75%. Also, studies on stomach and esophageal cancers, sponsored by the National Cancer Institute, showed that over 5 years, those who took a combination of beta-carotene, vitamin E, and selenium (another antioxidant found in seafood, liver, grains and seeds grown in selenium-rich soil) had a 13% reduction in the total death rate than those who did not use the antioxidants. This study also showed a 45% reduction in lung cancer. Although recent studies have shown that high doses of vitamin E (more than 100 International Units a day) and beta-carotene (more than 17,000 IU a day) supplements have adverse side effects or even reverse effects on the prevention of cancer, this is not the case with ordinary vitamin E-rich or carotene-rich foods. Therefore, it is highly suggested that one stick to eating the required amount of fruits and vegetables per day to not only help prevent cancer, but because of the many other health benefits these antioxidant-rich foods yield. Finally, future studies should determine the effects these antioxidants have on cigarette smokers and breast cancer.
1) Frei, Belz. "Reactive Oxygen Species and Antioxidant Vitamin: Mechanisms of Action." American Journal of Medicine, Sep 26, 1994, v97n3A, p. 6S.
2) van Holde, K.E. and Mathews, Christopher. Biochemistry. The Benjamin/Cummings Publishing Company, Inc, 1990
Antioxidants are similar to and affect steroid hormones. Vitamin D is considered an antioxidant yet it is also considered a prohormone because it is converted to a metabolite that acts like a steroid hormone. Its action involves the regulation of calcium and phosphorous metabolism, particularly with respect to synthesis of the inorganic matrix of bone, which consists largely of calcium phosphate.
Terpene is a generic term for all compounds that are biosynthesized from isoprene precursors. Therefore, cholesterol, steroids, and lipid-soluble vitamins are terpenes; they are significant because of their importance in animal metabolism. Tetraterpenes are biosynthesized from Terpenes, all that to say that tomato pigment (tetraterpene) is almost identical to beta-carotene which is an antioxidant.
Antioxidants seem to play an important role in our bodies due to their ability to share an electron that stops the free radical process; therefore, they relate to almost any subtopic in that they are physically present and stop, inhibit, or break a negative reactions in our body.
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At the end of the mitochondrial respiration chain, in aerobic organisms, oxygen is reduced to water. Further upstream in the mitochondrial respiratory chain, there is leakage of electrons from nonheme iron-sulfur proteins, leading to only a partial reduction of O2 to the superoxide anion 02.-, a reactive radical because it is unstable and wants to fulfill its octet. The leakage of electrons from the mitochondrial respiratory chain occurs continuously. 1-2% of the electrons in the respiratory chain do not make to complex IV and leak out to form O2.- and H202. There are other biological process that produce O2, cytochrome P-450 is an example.
Cytochrome P-450 is a family of heme proteins that are involved in numerous hydroxylation reactions. They are found in the endoplasmic reticulum and resembel mitochondrial cytochrome because it is able to bind to both O2 and CO2. Cytochromes P-450 are involved in hydroxylating a large variety of compounds such as hydrocarbon groups of fatty acids, steroid rings, and carcinogens such as benzpyrene. They are also partially responsible for the activation of potentially carcinogenic substances. The figure below shows the interconversion of reactive oxygen species.
Electron transport chains
(1010molecules/cell/day
Oxidases (NADPH, amino
0.15 mol/day 1.75kg(4lbs)
acid, xanthinine, etc.)
Cytochrome P-450 ---------> O2.-
2O2.- + 2H+ ---------> H2O2 + O2
02.- + H202 + H+ ----------> O2 + HO. + H20
(O2.- + Fe3+ -----------> O2 + Fe2+
H202 + H+ Fe2+ ---------> HO. + H2O + Fe3+
HO. + O2.- + H+ ---------> 1O2 + H20
Each cell in the human body is exposed to 100,000,000,000 molecules of the superoxide anion every day. Because of this, antioxidants are necessary to prevent oxidative damage to our cells, DNA, or proteins. Antioxidants will prevent the radical anion from forming by donating electrons to stabilize it. Studies have shown that free radicals such as the superoxide anion play a significant role in the formation of artherosclerosis because they inhibit oxidation of LDL on arterial walls.
As noted in the diagram (refer to fig 2), on the formation of free radicals, metalloenzymes are indirectly related to antioxidants. To mention one example, metals such as ferric or cupric ions (Fe3+ or Cu2+) can function as metal catalysts in a metal-catalyzed reaction called the "Haber-Weiss reaction." This reaction is really the sum of two separate ones. The first is the reduction of ferric or cupric ions by the superoxide radical (O2*-). The second is the reaction of the reduced metal ions, ferrous (Fe2+) or Cuprous (Cu+) with hydrogen peroxide to yield the dangerous hydroxyl radical. This latter reaction is called the "Fenton reaction."
Thus, as mentioned in the regulation portion of the antioxidant discussion, the body then uses a protective response to convert the free radicals, such as the hydroxyl radical, into harmless molecules. Cellular enzymes such as superoxide dismutates can convert the radicals into hydrogen peroxide and then into harmless oxygen and water. Antioxidant vitamins and beta-carotene (a precursor to vitamin A) can then assist the cell's enzymes by donating their electrons to the free radical. Once again, this process prevents free radicals from carrying out their harmful effects which can lead to cell damage, cell death, complete breakdown of the cell membrane, and/or eventually diseases, some of which can be fatal (e.g. cancer, as mentioned in the antioxidant discussion).
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