|Year : 2014 | Volume
| Issue : 4 | Page : 221-230
Antioxidant supplementation for health - a boon or a bane?
Uppala Satyanarayana1, Amar Nagesh Kumar2, Jupalle Nagaiah Naidu2, Devavarapu Kasi Viswa Prasad3
1 Department of Biochemistry, Dr. Pinnamaneni Siddhartha Institute of Medical Sciences and Research Foundation, Chinaoutapalli, Gannavarm, Krishna District, India
2 Department of Biochemistry, Narayana Medical College, Nellore, India
3 Department of Molecular Biology, Institute of Genetics and Hospital for Genetic Diseases, Hyderabad, Telangana, India
|Date of Web Publication||10-Dec-2014|
Dr. Pinnamaneni Siddhartha Institute of Medical Sciences and Research Foundation, Chinaoutapalli, Gannvaram, Krishna District - 521 286, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Antioxidants (vitamins E and C, β-carotene, superoxide dismutase [SOD], catalase etc.) are the substances that protect cells from the damage caused by free radicals, formed as a result of oxidative stress. Free radicals (O 2− , H 2 O2, OH− , ROO− etc.) are generated during the cellular metabolism and also due to environmental effects (cigarette smoke, ionizing radiations). Excessive production of free radicals has been implicated in the causation and progression of several diseases, e.g., atherosclerosis, cancer, rheumatoid arthritis, diabetes, and cataract. The general belief is that since free radicals are bad for health, antioxidants are good. This led to an indiscriminate use and supplementation of antioxidants, which is currently a controversial issue. This review gives an updated information on the effects of supplementation of antioxidants (vitamins E and C, β-carotene, SOD, catalase etc.). While some studies suggest that antioxidants are beneficial and protective, other interventional trials showed no health benefits. There are some interventional studies which demonstrated the deleterious effects of antioxidants (high risk of cancer, increased mortality). Further, antioxidant supplements were found to diminish the beneficial effects of certain drugs. It is suggested that indiscriminate use of antioxidant supplements should be avoided. Perhaps, antioxidants may be prescribed (not exceeding the recommended daily allowance) to the elderly, strict vegetarians or people who are on calorie-restricted diets. It is advisable that the antioxidants are consumed from rich natural dietary sources rather than supplements. Further, healthy individuals should exercise utmost caution while overdosing themselves with antioxidant supplements.
Keywords: Antioxidants, oxidative stress, free radicals, antioxidant supplements
|How to cite this article:|
Satyanarayana U, Kumar AN, Naidu JN, Viswa Prasad DK. Antioxidant supplementation for health - a boon or a bane?. J NTR Univ Health Sci 2014;3:221-30
|How to cite this URL:|
Satyanarayana U, Kumar AN, Naidu JN, Viswa Prasad DK. Antioxidant supplementation for health - a boon or a bane?. J NTR Univ Health Sci [serial online] 2014 [cited 2019 Apr 22];3:221-30. Available from: http://www.jdrntruhs.org/text.asp?2014/3/4/221/146595
| Introduction|| |
An antioxidant is basically 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.
Free radicals exist as independent molecular species, generated by normal biological process (cellular metabolism) and environmental effects. Free radicals are extremely unstable, energy rich entities due to the presence of unpaired electrons. This is the reason why they are so quick to take part in chemical reactions and responsible for the damage of biomolecules. This in turn may form the basis for several diseases, e.g., atherosclerosis, cancer, respiratory disorders, rheumatoid arthritis, diabetes, and cataract.
Our body has natural defense system against the free radicals. Antioxidants are substances that protect cells from the damage caused by unstable free radicals. Antioxidants interact with and stabilize free radicals and may prevent some of the damages caused by free radicals. Examples of antioxidants include vitamins A (β-carotene), C and E, lycopene, reduced glutathione (GSH), thiols, and other antioxidant enzymes.  Higher intakes of antioxidant-rich foods (fruits, vegetables etc.) may help in protecting from oxidative damage, thus lowering risk for cardiovascular disease (CVD) and different types of cancer.  Epidemiologic studies have consistently found that a diet rich in fruits and vegetables is associated with reduced risk for cancer, CVD, etc. Increased intake of fruits and vegetables may thus provide a defense against oxidative stress, a potential target for preventing diseases. , The beneficial effects of antioxidants have led to their overuse in recent years, particularly in the form of supplements (other than dietary). This practice has become controversial in view of recent evidence associated with increased risk of cancer and mortality. The present review provides information on oxidative stress, free radicals, along with their beneficial and harmful effects, besides the use and misuse of antioxidant supplements.
| Oxidative stress|| |
The oxygen consumed is utilized by mitochondria for oxidative phosphorylation and is reduced to water in the electron transport chain. A small fraction of it, not used for this purpose, is converted into free radicals that are harmful to the body when present in excess. Free radicals are harmful to the body because they contain an unpaired electron in their structure. These oxygen particles with an unpaired electron are collectively called as reactive oxygen species (ROS) and are proven to cause cell and tissue injury. They are also responsible for certain diseases and to some extent the aging process. Different types of ROS are continuously formed in vivo, and many of them are powerful oxidizing agents, capable of damaging DNA and other biomolecules. Increased formation of ROS can promote the development of malignancy, and the abnormal rates of ROS generation may account for the increased risk of cancer development in the aged. Indeed, knockout of various antioxidant defense enzymes raises oxidative damage levels and promotes age-related cancer development. 
| Sources and generation of reactive oxygen species/free radicals|| |
The major sources responsible for the generation of free radicals may be considered under two categories:
- Due to normal biological process (or cellular metabolism)
- Due to environmental effects.
By definition, a free radical contains one or more unpaired electrons. e.g., O 2− , OH− , ROO− . There are certain nonradical derivatives of oxygen which do not contain unpaired electrons. e.g., H 2 O 2 , 1 O 2 .The term ROS is used in a broad sense to collectively represent free radicals and nonfree radicals (which are extremely reactive) of the biological systems.  Radical formation is a spillover of the respiratory metabolism in the mitochondria of the cell. There are several mechanisms that can lead to the generation of free radicals. During the process of oxidative phosphorylation in the mitochondria, oxygen is used to form adenosine triphosphate. Little amount of oxygen can leak out and bind with free single electrons from the respiratory chain and later form superoxide radical (O 2− ). These superoxide radicals (O 2− ) can lead to the formation of hydrogen peroxide (H 2 O 2 ) and the highly reactive hydroxyl radical (OH− ).  It is estimated that a minimum of 1% and a maximum of 40% of the O 2 taken up by the body is converted to free radicals.
Another way of production of free radicals is through inhalation of environmental pollutants, such as NO 2 and ozone. The air can be a direct source of free radicals, for example, nitrogen dioxide, or as an indirect source through the highly reactive pollutants such as ozone. Strenuous exercise induces free radical formation in muscles and in the liver that will lead to oxidative damage such as lipid peroxidation. This damage caused by oxidative stress can be reduced by taking dietary supplements of different antioxidants, such as vitamin E, vitamin C and carotenoids.
| Beneficial effects of free radicals|| |
Free radicals play an important physiological role to sustain life. They participate in the metabolism of endogenous and exogenous lipids, in cellular respiration, in the production of prostaglandins and leukotrienes by arachidonic acid, in phagocytosis and in the immune response.  During the course of phagocytosis, inflammatory cells, particularly the macrophages produce superoxide (O 2− ), by the reaction catalyzed by NADPH oxidase. This superoxide (O 2− ) radical gets converted to H 2 O 2 and then to hypochlorous acid (HClO). The superoxide (O 2− ) radical along with hypochlorous ions brings about bactericidal action. This truly represents the beneficial effects of the free radicals generated by the body. A large amount of O 2 is consumed by macrophages during their bactericidal function, a phenomenon referred to as a respiratory burst [Figure 1].
|Figure 1: Benefi cial effects of free radicals — generation of free radicals by macrophages and respiratory burst|
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Perhaps free radicals, at least for most of our lifespan, may not pose a great threat to our wellbeing unless we expose ourselves to an excess of free radical-generating agents such as cigarette smoke or ionizing radiation, etc. ,
| Harmful effects of free radicals|| |
Free radicals are highly reactive because of unpaired electron present in their atomic structure. They are capable of damaging biomolecules-lipids, proteins, carbohydrates and nucleic acids. As already mentioned earlier, free radicals once formed in the biological system will continuously generate free radicals by chain reaction. They damage the membranes, cells, and even tissues.
Polyunsaturated fatty acids (PUFA) are highly susceptible to damage by free radicals.
Free radical induced peroxidation of membrane lipids occurs in three stages - initiation, propagation and termination.
This step involves the removal of the hydrogen atom (H) from PUFA (LH), caused by hydroxyl radical.
Under aerobic conditions, the fatty acid radical (L− ) takes up oxygen to form peroxy radical (LOO− ). The latter in turn, can remove H− atom from another PUFA (LH) to form lipid hydroperoxide (LOOH). The hydroperoxides are capable of further stimulating lipid peroxidation as they can form alkoxy (LO− ) and peroxyl (LOO− ) radicals.
Lipid peroxidation proceeds as a chain reaction until the available PUFA gets oxidized. 
Products of lipids peroxidation are unstable. e.g., carbonyls, esters, alkanes, alkenes, 2-alkenal, 2,4- alkadienal, malondialdehyde (MDA). Of these, MDA is the most extensively studied, and is used as a biochemical marker for the assessment of lipid peroxidation. The estimation of serum MDA is often used to assess oxidative stress, and free radical damage to the body. 
Free radicals can cause oxidation of the sulfhydryl group of sulfur containing amino acids present in the biologically active proteins. ROS may damage proteins by fragmentation, cross linking and aggregation. This leads to conformational changes in the proteins and their loss of biological activity.
Glycation of proteins present in cells increases the susceptibility of proteins to the attack by free radicals. This explains the reason for major complications (like diabetic retinopathy, diabetic nephropathy etc.) associated with diabetes mellitus. Reactive species (RS) of various types are formed in vivo and many are powerful oxidizing agents, capable of damaging DNA and other biomolecules. Increased formation of RS can promote the development of malignancy, and the normal rates of RS generation may account for the increased risk of cancer development in the aged. Indeed, knockout of various antioxidant defense enzymes raises oxidative damage levels and promotes age-related cancer development in animals. 
Excessive generation of free radicals in vivo is associated with various diseases, for example, oxidized low density lipoproteins formed by the action of free radicals will promote atherosclerosis. It is also proved that free radicals are associated with certain inflammatory diseases like rheumatoid arthritis and respiratory disorders [Figure 2].
|Figure 2: Production and harmful effects of free radicals (NO: Nitric oxide; IL: Interleukins; ROS: Reactive oxygen species; RNS: Reactive nitrogen species)|
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It is well known that in diabetes mellitus, there is increased oxidative stress and accumulation of ROS. This can lead to the development of cataract in elderly people. Free radicals may also be responsible for male infertility and aging process. 
| Body antioxidant defense system|| |
As a defense against the harmful effects of ROS, certain individuals use artificial supplementation of antioxidant enzymes. There are two main lines of endogenous defense in humans against the detrimental effects of ROS/reactive nitrogen species (RNS). The first line of defense consists of antioxidant enzymes like superoxide dismutase (SOD), catalase and GSH peroxidase. The second line of defense includes lipophilic and hydrophilic antioxidants such as vitamin E, vitamin C, vitamin A (β-carotene), ceruloplasmin, etc. 
| Antioxidant enzymes|| |
It converts superoxide (O 2− ) to hydrogen peroxide (H 2 O 2 ) and O 2 . Three forms of SOD are found in human tissues. They are:
- SOD with copper and zinc, found in cytoplasm and organelles of almost all human cells.
- SOD with manganese, mainly distributed in mitochondria.
- Extracellular SOD contains copper and zinc, synthesized by fibroblasts and endothelial cells. 
Hydrogen peroxide produced by SOD is removed by catalase. It is mostly found in the peroxisomes. ,
It catalyzes the oxidation of the reduced GSH to oxidized glutathione (GS-SG). Activity of GSH peroxidase depends on the selenium. ,
| Antioxidant nutrients|| |
Vitamin related antioxidants include vitamins E and C, and carotenoids.
Vitamin E is a collective name for numerous different tocopherols and tocotrienols which share the same biological activity. Vitamin E is a fat soluble substance and is a major antioxidant in all cellular membranes and protects PUFA against oxidation. 
Ascorbic acid is a water-soluble vitamin. It is believed to be the most important antioxidant in cellular fluids, and it has many known intracellular activities and many preventive effects in other medical conditions as well. 
The carotenoids are a group of red, yellow and orange pigments found in plant foods, particularly fruits and vegetables and in the tissues of animals which eat these plants. Some carotenoids can act as precursors of vitamin A. 
Nutrition has a key role in maintaining the body's defense mechanism against free radicals. A proper diet with adequate intake of antioxidants is important in the prevention of disease and promotion of optimal health and wellbeing. The best known dietary antioxidants are vitamin E, vitamin C and carotenoids etc., [Table 1].  Some foods contain substances with no nutritional function, but they are important to human health because of their antioxidant property e.g., resveratrol found in red wine.
| Classification of antioxidants|| |
Antioxidants are divided into two groups:
- Primary or natural antioxidants.
- Secondary or synthetic antioxidants.
Primary or natural antioxidants
They are the chain-breaking antioxidants which react with lipid radicals and convert them into more stable products. Antioxidants of this group are mainly phenolic in structures and include the following: 
- Antioxidant minerals - These are cofactors of antioxidants enzymes. Their absence will adversely affect metabolism of many macromolecules such as carbohydrates. Examples include selenium, copper, iron, zinc and manganese.
- Antioxidant vitamins - They are needed for most body metabolic functions. They include vitamin C, vitamin E.
- Phytochemicals - These are phenolic compounds. e.g., flavonoids; carotenoids; lycopene, etc.
Secondary or synthetic antioxidants
These are synthetic phenolic compounds that perform the function of capturing free radicals and stopping the chain reactions. The most important among these are listed below: 
- Butylated hydroxyl anisole (BHA).
- Butylated hydroxy toluene (BHT).
- Propyl gallate and metal chelating agent (ethylenediaminetetraacetic acid).
- Tertiary butyl hydroquinone.
- Nordihydro guaretic acid.
Synthetic antioxidants are used to preserve edible fats and oils from becoming rancid, and to prevent fruit and vegetables from turning brown. Examples include BHA and BHT, ascorbic acid (vitamin C), α-tocophenol (vitamin E). Hence, vitamins containing aromatic ring which reacts and destroys the most reactive forms of oxygen radicals, protecting the most unsaturated fatty acids from oxidation and preventing oxidative damage to the membrane. ,
| Antioxidants and health benefits|| |
A healthy cell has a mortal enemy which is called a "free radical." Free radicals constantly leak out healthy cells and attack their vulnerable outer membranes eventually causing cellular degeneration and death. The body has developed several endogenous antioxidant systems to deal with the production of RS (ROS/RNS). These systems can be divided into enzymatic and nonenzymatic groups. 
The enzymatic antioxidants namely SOD, catalase and glutathione peroxidase are important. SOD catalyzes the conversion of O 2−/O− to H 2 O 2 and O2 . Catalase then converts H2 O2 to H2 O and O2 . GSH peroxidase reduces H2 O2 to H2 O. ,
The nonenzymatic antioxidants include the lipid-soluble vitamins, vitamin E and vitamin A or provitamin A (β-carotene) and the water-soluble vitamin C. Vitamin E has been described as the major chain-breaking antioxidant in humans. It is located within the membranes, where it interrupts lipid peroxidation and may play a role in modulating intracellular signaling pathways that rely on ROS. Vitamin E can also directly quench free radicals. 
When vitamin E-deficient rats were fed either α-tocopherol or α-tocotrienol enriched diets, tocotrienol accumulated in the hearts and liver more slowly than α-tocopherol. The rate of lipid peroxidation induced in vitro in heart homogenate from rats supplemented with α-tocotrienol was approximately two-thirds as high as that of α-tocopherol. Thus, palm oil vitamin E may be more efficient than α-tocopherol alone in protecting the heart against injury from ischaemia and reperfusion. 
In addition, supplementation with α-tocopherol or α-tocotrienol protects skeletal muscles against exercise induced increases in protein oxidation. Thus by palm oil vitamin E protects biological systems against both lipid and protein oxidation. The pathogenesis of many diseases can involve free radical-mediated lipid peroxidation in biological membranes. Vitamin E is the major chain-breaking antioxidant in membranes although it is present in extremely low concentration. It is very efficient in inhibiting the development of conditions such as heart disease, cancer, cataracts, neuropathies and myopathies and other related diseases. 
The destructive effects of free radicals can be prevented with the addition of antioxidants in the diet or by antioxidant supplements. A good antioxidant complex supplement actually has advantages over diet sources in that the complex has many different specific types of antioxidants which seek out and destroy free radicals at many cellular sites. A single antioxidant, for example, vitamin E, only protects the outer fatty layers of the cell. It will not stabilize DNA which, for example, is one of the main effects of the antioxidant vitamin C. The process by which different antioxidants disperse through the bloodstream to protect the cells at different sites are referred to as "antioxidant synergy." When a specific antioxidant meets a free radical in the bloodstream at its appropriate activity site, it naturally combines with it and coverts the free radical to harmless water and oxygen. As a result, as antioxidant increases due to the supplementation of higher amounts of a greater variety of antioxidants, cellular damage lessens, and performance and health improves. 
Mounting evidence from human studies points to the action of free radical species in the pathogenesis, and to the potential efficacy of vitamin C, vitamin E, and β-carotene in reducing the risk of cancer, degenerative eye disorders, and CVD. For example, in both the health professionals follow-up study and the nurses' health study supplementary intakes of vitamin E were associated with a reduced coronary heart disease risk of 40%. , Preliminary examination of the established populations for epidemiologic studies of the elderly revealed a reduction in coronary heart disease risk of 69% in older adults consuming supplements of vitamins C and E and of 58% in those taking vitamin E supplements only.  Robertson et al. found that people consuming supplements of vitamin C, vitamin E, or both appear to have a 40-75% reduction in the risk of developing cataracts. 
The consumption of berries has diverse health benefits such as prevention of stroke, age-related degenerative diseases and cancer. Some berry constituents have cancer suppressive effects. Certain phytochemicals present in berries have high antioxidative potentials that could contribute to, or enhance by induction, the endogenous antioxidant properties of living cells or organisms. 
Till 1990, scientists were confident about the beneficial effects of antioxidants. In late 90's, researchers began to conduct very large-scale studies (involving tens of thousands of participants) to determine the benefits of antioxidants in fairly high doses. The α-tocopherol, β-carotene, and cancer prevention study (ATBC), the physicians' health study, the β-carotene and retinol efficacy trial (CARET), and the skin cancer prevention study were among these large-scale studies. The unexpected result in several of these studies was the fact that antioxidant dietary supplements actually increased the risk of disease instead of lowering it. With these studies what we are now realizing is that, antioxidants may not be having beneficial role. Further every antioxidant can become a pro-oxidant that is, it can reverse its role in our metabolism.
| Supplementation of artificial antioxidants versus natural antioxidants|| |
Many people take daily supplements that include antioxidants such as vitamins A, C, and E, β-carotene, coenzyme Q 10 , and α-lipoic acid thinking that the supplementation with antioxidants is an effective way to neutralize harmful free radicals. This has been shown in both epidemiological studies and observational studies. Even though, it is known that antioxidants can be obtained from food the consumption of antioxidant supplements in the general population is broad in extent. Many people are taking antioxidant supplements to supplement the natural antioxidant intake from their diet to improve the free radical scavenging activity in their bodies as a way to prevent health problems and prevent the development of disease states or otherwise to slow down the aging process or slow down the progression of disease conditions that are free radical induced.  A growing number of researchers have noticed that there is an industry-driven public obsession with antioxidants, which are equated to safe, health-giving molecules to be swallowed as mega-dose supplements or in fortified foods.  More recent theories suggest that certain vitamins consumed as part of a healthy diet, and perhaps taken in supplement form may be able to prevent damage to the body's tissues. This damage has been implicated in several major diseases including cancer and heart disease, yet the implication that vitamin supplements might protect people from these illnesses is controversial. As a defense against the detrimental effects of ROS/RNS, a growing number of individuals use high doses of antioxidants (artificial supplements), and since there are few human studies, it is difficult to know the proper dosage to take. 
One of the strongest arguments for taking antioxidant supplements is the observation that consumption of fruits and vegetables reduces the levels of oxidative damage and associated degenerative diseases. The assumption has always been that these benefits can be attributed to the fact that many fruits, vegetables and herbs are rich sources of naturally occurring antioxidants. Therefore, it only makes sense that if one cannot get enough fruits and vegetables in their normal diet, supplementation with purified chemical forms of these antioxidants can boost those benefits. However, it turns out that the protective effects of fruits and vegetables are most likely not due to their antioxidant content alone, which is probably too weak and inconsistent to explain the health benefits. Selecting an antioxidant dose too high may result in unacceptable safety problems, while selecting a dose too low may lead to ineffectiveness.  Widespread use of antioxidant supplements/enzymes has failed to quell the current pandemic of cancer, diabetes, and CVD or to stop or reverse the aging process. 
| Harmful effects of antioxidant supplements|| |
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.  While reviewing the existing literature, we found numerous clinical trials and metabolic studies to show that no benefit, or even harm, due to antioxidant supplements. So antioxidant supplements are probably ineffective, or they may even be hazardous to our health. In this section, we describe some studies that indicate the supplementation of antioxidants might be harmful.
Two main large interventional studies raised the spectrum that some antioxidants may have deleterious health effects. The CARET studied 18,314 men and women at high risk of lung cancer. Participants received either a combination of 30 mg of β-carotene and 25,000 IU of vitamin A daily or placebo.  Summary of the study is - the group taking the supplement had a statistically significant 28% higher incidence of lung cancer and 17% more deaths than the placebo group. Similar concerns were raised in the ATBC study.  In this study, 29,133 male smokers age 50-69 were assigned to treatment with α tocopherol 50 mg daily or β-carotene 20 mg daily or a combination of either vitamins or placebo. Results of this study showed that the total mortality rate was 8% higher (a statistically significant difference) in the group taking β-carotene compared with those who did not receive β-carotene, primarily due to more deaths from lung cancer.
University of Washington randomized trial showed evidence of positive harm from antioxidants. A cocktail of antioxidants added to the course of patients with high cholesterol and using statin-niacin therapy led to reduced levels of high-density lipoprotein (HDL) and increased levels of coronary blockage.  In HDL atherosclerosis treatment study (HATS), it was found that antioxidants diminished the beneficial effects of simvastatin plus niacin. It was further reported the niacin induced elevation of HDL-2 was blunted by antioxidants. 
The American Heart Association meta-analysis of 20 clinical trials showed no benefits for the use of vitamins C, E and β-carotene in the prevention of heart attacks or strokes, and no reduction in mortality. While they acknowledged that the scientific evidence from observational studies supports the conclusion that "a diet high in food sources of antioxidants and other cardioprotective nutrients" reduces the risk of CVD, they found no support for any benefits from the use of antioxidant vitamin supplements.  They did indicate that antioxidant supplementation may be useful in certain critical medical procedures, but not for routine dietary supplementation.
A study at Cedars-Sinai Heart Institute showed that cardiac stem cells that were loaded with high doses of antioxidants developed genetic abnormalities that predispose to the development of cancer. 
A study comparing chemical vitamin C and oranges containing an equivalent amount of vitamin C given to test subjects showed that the blood from those who ingested the oranges could neutralize hydrogen peroxide (an oxidant) but those who ingested vitamin C tablets failed to do so. 
A study by German and American researchers found that daily supplementation with 1000 mg vitamin C and 400 IU vitamin E during a 4-week exercise program by healthy young men suppressed improvements in insulin sensitivity observed in the nonsupplementing control group.  Thus, supplementation with antioxidants may preclude health promoting effects of exercising humans.
Other Linxian study was cancer therapy by taking β-carotene (15 mg), vitamin E (30 mg), selenium (Se, 50 μg) in 1993 using 29,584 cancer patients (aged between 40 and 69 years) in China for 5 years survey and it resulted that slight decrease of cancer risk (relative risk: 0.91, 95% confidence interval: 0.84-0.99, P < 0.03). Selenium may or may not be effective. 
Vitamins C and E and β-carotene supplementation and cancer risk
A randomized controlled trial-proved that long-term dietary supplementation with any combination of the antioxidants-vitamin C, vitamin E, or β-carotene does not reduce the risk of cancer or the risk of dying from cancer. Further, in this study they concluded that there is no basis for a recommendation that individuals increase dietary levels of antioxidants as a means of reducing cancer risk. 
Excessive antioxidant action can adversely affect key physiological processes. ,, It has been shown that over-consumption of antioxidant enzymes could down-regulate their own endogenous production.  An interesting study indicated that blood SOD decreased following oral administration of plant SOD to healthy subjects. 
A recent meta-analysis by Cochrane institute on 78 randomized trials with 2,96,707 participants antioxidant supplements (β-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo, found no beneficial effects. They concluded that they did not find any evidence to support antioxidant supplementation for primary or secondary disease prevention in healthy people or patients with various diseases. 
Thus, data from the recent studies on humans demonstrate that antioxidant supplementation has no beneficial effect in the treatment of diseases like cancer, CVD in the long run. Further, it may be stated that supplementation of certain antioxidants like β- carotene, vitamin E, in high doses, appear to increase mortality rate. ,,,
In a very recent study,  it was reported that the mice fed with a diet supplementing with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increased tumor progression and reduced survival in mouse models of B-RAF and K-RAS-induced lung cancer. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production. 
So flooding the biological system with antioxidants or the over use of antioxidative enzymes may be just as detrimental as excessive exposure to free radicals.  In fact, various ROS-mediated actions protect cells against ROS-induced oxidative stress. Very high doses of antioxidants could produce harmful effects on cellular signaling processes. For example, ROS can induce the release of arachidonic acid and activate tyrosine kinases and mitogen-activated protein kinases, which are critical components of many intracellular signaling cascades, including those required for cell survival and growth. Thus, antioxidant supplementation could potentially be harmful to those tissues that are not subjected to substantial oxidative stress. 
Moreover, over-consumption of antioxidants (including enzymes) could down regulate important endogenous antioxidants, depress parts of the immune system, or perhaps increase microbial damage or the normal cellular protective responses to tissue damage.  Double-edged effects of exogenous antioxidants on cellular responses including oxidative, nitrosative and dicarbonyl metabolisms and other pathways depending potentially on their concentrations: Physiologic doses leading to beneficial effects whereas high doses may result in harmful effects. 
As such, antioxidants supplementation becomes doubtful in its usefulness, and thus creates a big confusion. Hence it appears that, by consuming more antioxidants, we are likely to become dependent upon them and perversely reduce our innate ability to detoxify free radicals. Therefore, although certain supplements have been thoroughly researched and have known beneficial effects, healthy individuals should take them with caution, in view of the recent findings of their harmful effects. With any let-up in the constant supply of external defenses, we become more vulnerable to oxidative stress. Externally supplied antioxidants themselves are in any case much less effective than the endogenous ones. So antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation.
| Conclusions|| |
The health benefits of antioxidant supplementation are controversial and many a times confusing the clinicians because the results of some studies conflict with others. Hence making simple conclusions as to efficacy and safety is very difficult. An evidence-based approach should focus on the need to answer the myriad questions surrounding pro and antioxidative mechanisms of action associated with antioxidant use, and what effects dose and environment have on these mechanisms before recommending nutritional or pharmacological interventions.
The key to the future success of decreasing oxidative stress induced damage should thus be the suppression of oxidative damage without disrupting the well-integrated antioxidant defense network. Finally, it is worthwhile to take a step back and consider that reversible health behaviors, such as smoking habit and overeating combined with a sedentary lifestyle, contribute far more to the risk for various diseases including cancer than may be improved with any antioxidant supplementation. Supplementation with vitamin C, vitamin E, or β-carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality. There is widespread antioxidant availability, extensive antioxidant food advertising, and pervasive promotion of antioxidants in the media. In these circumstances, patient safety must remain the number one concern. Until scientifically tested, treatment modalities should always place patient safety first. Thus, based on current data and theoretical considerations, the excessive supplementation of antioxidants appears to pose unnecessary dangers and could harbor considerable potential for harm.
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