The body has several mechanisms to counteract oxidative stress by producing antioxidants, either naturally generated in situ (endogenous antioxidants), or externally supplied through foods (exogenous antioxidants). The roles of antioxidants are to neutralize the excess of free radicals, to protect the cells against their toxic effects and to contribute to disease prevention.
Endogenous compounds in cells can be classified as enzymatic antioxidants and non-enzymatic antioxidants.
The major antioxidant enzymes directly involved in the neutralization of ROS and RNS are: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GRx) (6-12). SOD, the first line of defense against free radicals, catalyzes the dismutation of superoxide anion radical (O2•–) into hydrogen peroxide (H2O2) by reduction. The oxidant formed (H2O2) is transformed into water and oxygen (O2) by catalase (CAT) or glutathione peroxidase (GPx). The selenoprotein GPx enzyme removes H2O2 by using it to oxidize reduced glutathione (GSH) into oxidized glutathione (GSSG). Glutathione reductase, a flavoprotein enzyme, regenerates GSH from GSSG, with NADPH as a source of reducing power. Besides hydrogen peroxide, GPx also reduces lipid or nonlipid hydroperoxides while oxidizing glutathione (GSH) (2, 5-10).
The non-enzymatic antioxidants are also divided into metabolic antioxidants and nutrient antioxidants. Metabolic antioxidants belonging to endogenous antioxidants, are produced by metabolism in the body, such as lipoid acid, glutathione, L-ariginine, coenzyme Q10, melatonin, uric acid, bilirubin, metal-chelating proteins, transferrin, etc (5, 6). While nutrient antioxidants belonging to exogenous antioxidants, are compounds which cannot be produced in the body and must be provided through foods or supplements, such as vitamin E, vitamin C, carotenoids, trace metals (selenium, manganese, zinc), flavonoids, omega-3 and omega-6 fatty acids, etc.
When an antioxidant destroys a free radical, this antioxidant itself becomes oxidized. Therefore, the antioxidant resources must be constantly restored in the body. Thus, while in one particular system an antioxidant is effective against free radicals, in other systems the same antioxidant could become ineffective. Also, in certain circumstances, an antioxidant may even act as a pro-oxidant e.g. it can generate toxic ROS/RNS (10). The antioxidant process can function in one of two ways: chain-breaking or prevention. For the chain-breaking, when a radical releases or steals an electron, a second radical is formed. The last one exerts the same action on another molecule and continues until either the free radical formed is stabilized by a chain-breaking antioxidant (vitamin C, E, carotenoids, etc), or it simply disintegrates into an inoffensive product. The classic example of such a chain reaction is lipid peroxidation. For the preventive way, an antioxidant enzyme like superoxide dismutase, catalase and glutathione peroxidase can prevent oxidation by reducing the rate of chain initiation, e.g., either by scavenging initiating free radicals or by stabilizing transition metal radicals such as copper and iron (10).
Antioxidants from our diet play an important role in helping endogenous antioxidants for the neutralization of oxidative stress. The nutrient antioxidant deficiency is one of the causes of numerous chronic and degenerative pathologies. Each nutrient is unique in terms of its structure and antioxidant function (6, 38).
Vitamin E. Vitamin E is a fat-soluble vitamin with high antioxidant potency. Vitamin E is a chiral compound with eight stereoisomers: α, β, γ, δ tocopherol and α, β, γ, δ tocotrienol. Only α-tocopherol is the most bioactive form in humans. Studies in both animals and humans indicate that natural dextrorotary d-α-tocopherol is nearly twice as effective as synthetic racemic dl-α-tocopherol (39). Because it is fat-soluble, α-tocopherol safeguards cell membranes from damage by free radicals. Its antioxidant function mainly resides in the protection against lipid peroxidation. Vitamin E has been proposed for the prevention against colon, prostate and breast cancers, some cardiovascular diseases, ischemia, cataract, arthritis and certain neurological disorders. (40). However, a recent trial revealed that daily α-tocopherol doses of 400 IU or more can increase the risk of death and should be avoided. In contrast, there is no increased risk of death with a dose of 200 IU per day or less, and there may even be some benefit (41). Although controversial, the use of long-term vitamin E supplementation in high dose should be approached cautiously until further evidence for its safety is available. The dietary sources of vitamin E are vegetable oils, wheat germ oil, whole grains, nuts, cereals, fruits, eggs, poultry, meat (6, 40). Cooking and storage may destroy natural d-α-tocopherol in foods (40).
Vitamin C. Vitamin C also known as ascorbic acid, is a water-soluble vitamin. It is essential for collagen, carnitine and neurotransmitters biosynthesis (42). Health benefits of vitamin C are antioxidant, anti-atherogenic, anti-carcinogenic, immunomodulator. The positive effect of vitamin C resides in reducing the incidence of stomach cancer, and in preventing lung and colorectal cancer. Vitamin C works synergistically with vitamin E to quench free radicals and also regenerates the reduced form of vitamin E. However, the intake of high doses of vitamin C (2000mg or more/day) has been the subject of debate for its eventual pro-oxidant or carcinogen property (42-43). Natural sources of vitamin C are acid fruits, green vegetables, tomatoes. Ascorbic acid is a labile molecule, therefore it may be lost from during cooking (43).
Beta-carotene, Beta-carotene is a fat soluble member of the carotenoids which are considered provitamins because they can be converted to active vitamin A. Beta-carotene is converted to retinol, which is essential for vision. It is a strong antioxidant and is the best quencher of singlet oxygen. However, beta-carotene supplement in doses of 20mg daily for 5-8 years has been associated with an increased risk of lung and prostate cancer and increased total mortality in cigarette smokers (44). Beta-carotene 20-30mg daily in smokers may also increase cardiovascular mortality by 12% to 26% (44). These adverse effects do not appear to occur in people who eat foods high in beta-carotene content. Beta-carotene is present in many fruits, grains, oil and vegetables (carrots, green plants, squash, spinach) (6).
Lycopene. Lycopene, a carotenoid, possesses antioxidant and antiproliferative properties in animal and in vitro studies on breast, prostate and lung cell lines, although anticancer activity in humans remains controversial (6, 45, 46). Lycopene has been found to be very protective, particularly for prostate cancer (46). Several prospective cohort studies have found associations between high intake of lycopene and reduced incidence of prostate cancer, though not all studies have produced consistent results (45). The major dietary source of lycopene is tomatoes, with the lycopene in cooked tomatoes, tomato juice and tomato sauce included, being more bioavailable than that in raw tomatoes (38).
Selenium (Se). Se is a trace mineral found in soil, water, vegetables (garlic, onion, grains, nuts, soybean), sea food, meat, liver, yeast (6). It forms the active site of several antioxidant enzymes including glutathione peroxidase. At low dose, health benefits of Se are antioxidant, anti-carcinogenic and immunomodulator (47). Selenium is also necessary for the thyroid function (48). Exceeding the Tolerable Upper Intake Level of 400 μg Se/day can lead to selenosis which is a selenium poisoning characterized by gastrointestinal disorders, hair and nail loss, cirrhosis, pulmonary edema and death (48). Selenium deficiency can occur in patients on total parenteral nutrition (TPN) and in patients with gastrointestinal disorders. In certain China areas with Se poor soil, people have developed a fatal cardiomyopathy called Keshan disease which was cured with Se supplement (48). The role of Se in cancer prevention has been the subject of recent study and debate. Results from clinical and cohort studies about cancer prevention, especially lung, colorectal, and prostate cancers are mixed (10, 48).
Flavonoids. Flavonoids are polyphenolic compounds which are present in most plants. According to chemical structure, over 4000 flavonoids have been identified and classified into flavanols, flavanones, flavones, isoflavones, catechins, anthocyanins, proanthocyanidins. Beneficial effects of flavonoids on human health mainly reside in their potent antioxidant activity (49). They have been reported to prevent or delay a number of chronic and degenerative ailments such as cancer, cardiovascular diseases, arthritis, aging, cataract, memory loss, stroke, Alzheimer’s disease, inflammation, infection. Every plant contains a unique combination of flavonoids, which is why different herbs, all rich in these substances, have very different effects on the body (50). The main natural sources of flavonoids include green tea, grapes (red wine), apple, cocoa (chocolate), ginkgo biloba, soybean, curcuma, berries, onion, broccoli, etc.
For example, green tea is a rich source of flavonoids, especially flavonols (catechins) and quercetin. Catechin levels are 4-6 times greater in green tea than in black tea. Many health benefits of green tea reside in its antioxidant, anticarcinogenic, antihypercholesterolemic, antibacterial (dental caries), anti-inflammatory activities (51).
Omega-3 and omega-6 fatty acids. They are essential long-chain polyunsaturated fatty acids because the human body cannot synthesize them. Therefore, they are only derived from food. Omega-3 fatty acids can be found in fat fish (salmon, tuna, halibut, sardines, pollock), krill, algae, walnut, nut oils and flaxseed. However, certain big fishes like tilefish, shark, swordfish are to be avoided because of their high mercury levels (52). There are three major dietary types of omega-3 fatty acids: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA). EPA and DHA are abundant in fish and are directly used by the body; while ALA is found in nuts and has to be converted to DHA and EPA by the body. Dietary sources of omega-6 fatty acids (linoleic acid) include vegetable oils, nuts, cereals, eggs, poultry. It is important to maintain an appropriate balance of omega-3s and omega-6s in the diet, as these two substances work together to promote health (52, 53). Omega-3 fatty acids help reduce inflammation, and most omega-6 fatty acids tend to promote inflammation. An inappropriate balance of these essential fatty acids contributes to the development of disease while a proper balance helps maintain and even improve health. A healthy diet should consist of about 2-4 times more omega-6s than omega-3s. In American diet, omega-6s are 14-25 times more abundant than omega-3s, that explains the rising rate of inflammatory disorders in the USA (52). Omega-3s reduce inflammation and prevent chronic ailments such as heart disease, stroke, memory loss, depression, arthritis, cataract, cancer. Omega-6s improve diabetic neuropathy, eczema, psoriasis, osteoporosis, and aid in cancer treatment (38, 52, 53).
Finally, some endogenous antioxidants such as L-arginine, coenzyme Q-10, melatonin are recently used as supplements for the prevention or treatment of some chronic and degenerative diseases (54-56). It is notified that the list of antioxidants cited here is not exhaustive.