Dr. Suja C Shuhaib.B, Muhammedabdurahman, Hunaidakhathoom , Simi K

A Review on Dietary Antioxidants

Dr. Suja C,, Shuhaib.B, MuhammedAbdurahman, Hunaidakhathoom , Simi k

Crescent College of Pharmaceutical Sciences, Madayipara, Payangadi R.S.(Post), Kannur, Kerala.

Abstract:

An antioxidant is a molecule stable enough to donate an electron to a rampaging free radical and neutralize it, thus reducing its capacity to damage. Mechanism of action of anti oxidant are a chain- breaking mechanism by which the primary antioxidant donates an electron to the free radical present in the systems and removal of ROS/reactive nitrogen species initiators by quenching chain-initiating catalyst. The article present a broad review on the dietary sources, several disease prevention by dietary anti oxidant .In this review study the cancer prevention, aspect of plant poly phenol as dietary anti oxidant in human health and the cardio protective effect, anti diabetic effect, anti aging effect , neuro protective effect are studied. From this review study we have come to the conclusion that dietary antioxidants are good for prevention of many of the lifestyle diseases, cancer etc as prevention is better than cure.

Key word: Anti oxidant, Mechanism, Poly phenol etc

Introduction:

Free radicals

A free radical can be defined as any molecular species capable of independent existence that contains an unpaired electron in an atomic orbital. The presence of an unpaired electron results in certain common properties that are shared by most radicals. Many radicals are unstable and highly reactive1. They can either donate an electron to or accept an electron from other molecules, therefore behaving as oxidants or reductants. Free radicals are derived either from normal essential metabolic processes in the human body or from external sources such as exposure to X-rays, ozone, cigarette smoking, air pollutants, and industrial chemicals. Free radical formation occurs continuously in the cells as a consequence of both enzymatic and nonenzymatic reactions. Enzymatic reactions, which serve as source of free radicals, include those involved in the respiratory chain, in phagocytosis, in prostaglandin synthesis, and in the cytochrome P-450 system. Free radicals can also be formed in nonenzymatic reactions of oxygen with organic compounds as well as those initiated by ionizing reactions.

An antioxidant is a molecule stable enough to donate an electron to a rampaging free radical and neutralize it, thus reducing its capacity to damage. These antioxidants delay or inhibit cellular damage mainly through their free radical scavenging property. These low-molecular-weight antioxidants can safely interact with free radicals and terminate the chain reaction before vital molecules are damaged. Some of such antioxidants, including glutathione, ubiquinol, and uric acid, are produced during normal metabolism in the body2. Antioxidants act as radical scavenger, hydrogen donor, electron donor, peroxide decomposer, singlet oxygen quencher, enzyme inhibitor, synergist, and metal-chelating agents.

Mechanism of action of antioxidants

Two principle mechanisms of action have been proposed for antioxidants. The first is a chain- breaking mechanism by which the primary antioxidant donates an electron to the free radical present in the systems. The second mechanism involves removal of ROS/reactive nitrogen species initiators (secondary antioxidants) by quenching chain-initiating catalyst. Antioxidants may exert their effect on biological systems by different mechanisms including electron donation, metal ionchelation, co- antioxidants , or gene expression regulation3.

Levels of antioxidant action

The antioxidants acting in the defence systems act at different levels such as preventive, radical scavenging, repair, and the fourth line of defence, i.e., the adaptation.The first line of defence is the preventive antioxidants, which suppress the formation of free radicals. Although the precise mechanism and site of radical formation in vivo are not well elucidated yet, the metal-induced decompositions of hydro peroxides and hydrogen peroxide must be one of the important source. The second line of defence is the antioxidants that scavenge the active radicals to suppress chain initiation and/or break the chain propagation reactions. Various endogenous radical-scavenging antioxidants are known: some are hydrophilic and others are lipophilic. Vitamin C, uric acid, bilirubin, albumin, and thiols are hydrophilic, radical-scavenging antioxidants, while vitamin E and ubiquinol are lipophilic radical-scavenging antioxidants. Vitamin E is accepted as the most potent radical-scavenging lipophilic antioxidant4.The third line of defense is the repair antioxidants. The proteolytic enzymes, proteinases, proteases, and peptidases, present in the cytosol and in the mitochondria of mammalian cells, recognize, degrade, and remove oxidatively modified proteins and prevent the accumulation of oxidized proteins.5

Types of antioxidants

Enzymatic

Cells are protected against oxidative stress by an interacting network of antioxidant enzymes. 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 dismutase’s catalyzing the first step and then catalases and various peroxidases removing hydrogen peroxide. Superoxide dismutase Superoxide dismutases (SODs) are a class of closely related enzymes that catalyze the breakdown of the superoxide anion into oxygen and hydrogen peroxide.SOD enzymes are present in almost all aerobic cells and in extracellular fluids6.

In humans three forms of superoxide dismutase are present. SOD1 is located in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular. The first is a dimer (consists of two units), while the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, while SOD2 has manganese in its reactive center7.Catalase is a common enzyme found in nearly all living organisms, which are exposed to oxygen, where it functions to catalyze the decomposition of hydrogen peroxide to water and oxygen. Hydrogen peroxide is a harmful by-product of many normal metabolic processes: to prevent damage, it must be quickly converted into other, less dangerous substances8. Glutathione systems include glutathione, glutathione reductase, glutathione peroxidases, and glutathione S-transferases. This system is found in animals, plants, and microorganisms. Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyze the breakdown of hydrogen peroxide and organic hydroperoxides

Nonenzymatic

Ascorbic acid------or “vitamin C” is a monosaccharide anti oxidant found in both animals and plants. As it cannot be synthesized in humans and must be obtained from the diet, it is a vitamin. Most other animals are able to produce this compound in their bodies and do not require it in their diets. In cells, it is maintained in its reduced form by reaction with glutathione, which can be catalyzed by protein disulfide isomerase and glutaredoxins.

Glutathione ------is a cysteine-containing peptide found in most forms of aerobic life. It is not required in the diet and is instead synthesized in cells from its constituent amino acids. Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibly oxidized and reduced.

Melatonin------also known chemically as N-acetyl-5-methoxytryptamine,is a naturally occurring hormone found in animals and in some other living organisms, including algae. Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood–brain barrier. Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of a molecule to undergo repeated reduction and oxidation 9

Tocopherols and tocotrienols------Vitamin E is the collective name for a set of eight related tocopherols and tocotrienols, which are fat-soluble vitamins with antioxidant properties. Of these, α-tocopherol has been most studied as it has the highest bioavailability, with the body preferentially absorbing and metabolizing this form. 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.

Uric acid------accounts for roughly half the antioxidant ability of plasma. In fact, uric acid may have substituted for ascorbate in human evolution. However, like ascorbate, uric acid can also mediate the production of active oxygen species

Literature review

Diet as a source of antioxidants

Synthetic and natural food antioxidants are used routinely in foods and medicine especially those containing oils and fats to protect the food against oxidation. There are a number of synthetic phenolic antioxidants, butylatedhydroxytoluene (BHT) and butylatedhydroxyanisole (BHA) being prominent examples. In view of increasing risk factors of human to various deadly diseases, there has been a global trend toward the use of natural substance present in medicinal plants and dietary plats as therapeutic antioxidants. It has been reported that there is an inverse relationship between the dietary intake of antioxidant-rich food and medicinal plants and incidence of human diseases. The use of natural antioxidants in food, cosmetic, and therapeutic industry would be promising alternative for synthetic antioxidants in respect of low cost, highly compatible with dietary intake and no harmful effects inside the human body. Many antioxidant compounds, naturally occurring in plant sources have been identified as free radical or active oxygen scavengers. Attempts have been made to study the antioxidant potential of a wide variety of vegetables like potato, spinach, tomatoes, and legumes.

The commonly used dietary antioxidant includes (with common/ayurvedic names in brackets) Alliumcepa (Onion), A. sativum (Garlic, Lahasuna),Amomumsubulatum (Greater cardamom, Bari elachi), Andrographispaniculata (Kiryat), Azadirachtaindica (Neem, Nimba), Bacopamonniera (Brahmi), Camellia sinensis (Green tea), Cinnamomumverum (Cinnamon),Curcmalonga (Turmeric, Haridra), Emblicaofficinalis (Inhian gooseberry, Amlaki),Mangiferaindica (Mango, Amra), Momordicacharantia (Bitter gourd), Murrayakoenigii (Curry leaf), Picrorrhizakurroa (Katuka), Piper beetle and Zingiberofficinalis (Ginger)10.

Cancer chemoprevention through dietary antioxidants

It was estimated that nearly one third of all cancer details in United States could be prevented through appropriate dietary modification. Various dietary antioxidants have shown considerable promise as effective agents for cancer prevention by reducing oxidative stress which has been implicated in the development of many diseases, including cancer. Therefore, for reducing the incidence of cancer, modifications in dietary habits, especially by increasing consumption of fruits and vegetables rich in antioxidants are increasingly advocated. This review presents an extensive analysis of the key findings from studies on the effects of dietary antioxidants such as, curcumin, lupeol, and pomegranate,against cancers of skin ,prostate,breast and liver .Cancer is a disease in which a series of cumulative and genetic changes that are initiated in a normal cell occur .Chemoprevention is a strategy to completely halt or slow the process of cancer development by intervening in the process of carcinogenesis.11

Curcumin

Curcumin is a major yellow pigment in turmeric that impartsa yellow colour to food and is widely used as a spice. It is derived from the roots of plant Curcuma longa. In MCF-7 breast cancer cells, telomerase activity decreased with increasing concentrations of curcumin, may be due to downregulation of hTERT expression. Curcumin caused a steady decrease in the level of human telomerase reverse Transcriptase (hTERT) mRNA in MCF-7 cells12.Curcumin inhibited camptothecin, mechlorethamine, and using a in vivo model of human breast cancer, dietary supplementation with curcumin was found to significantly inhibit cyclophosphamide-induced tumor regression which was accompanied by a decrease in activation of apoptosis by cyclophosphamide and decreased JNK (JUN N TERMINAL KINASE) activation.13

Pomegranate

The pomegranate (PunicagranatumL.) fruit has been used for centuries in ancient cultures for its medicinal purposes. Pomegranate fruits are widely consumed in fresh and beverage forms as juice.Ellagic acid, caffeic acid, luteolin, and punicic acid, all important components of the aqueous compartments or oily compartment of pomegranate fruit were reported to inhibit invitro invasion of human PC-3 prostate cancer cells in an assay employing matrigel artificial membranes. It was shown that PFE treatment of human prostate cancer PC-3 cells resulted in a dose dependent inhibition of cell growth/cell viability and induction of apoptosis14.

Lupeol

Lup-20-en-3-ol (Lupeol), a triterpene found in fruits such as such as olive, mango, strawberry, grapes, and figs, in many vegetables, and in several medicinal plants, is used in the treatment of various diseases. It possesses strong anti-inflammatory, antiarthritic, antimutagenic, and antimalarial activity invitro and in vivo systems. Lupeol has been shown to act as a potent inhibitor of protein kinases and serine proteases and to inhibit the activity of DNA topoisomerase II, a target for anticancer chemo therapy. It has also been reported to improve the epidermal tissue reconstitution and induces differentiation and inhibits the cell growth of melanoma cells.15Lupeol treatment resulted in significant inhibition of cell viabilityin a dose-dependent manner and caused apoptotic deathof prostate cancer cells. Lupeol was found to induce the cleavageof PARP protein and degradation of acinus protein with asignificant increase in the expression of FADD protein and Fasreceptor.16

Plant polyphenols as dietary antioxidants in human health and disease

Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In the last decade, there has been much interest in the potential health benefits of dietary plant polyphenols as antioxidant. Epidemiological studies and associated meta-analyses strongly suggest that long term consumption of diets rich in plant polyphenols offer protection against development of cancers, cardiovascular diseases, diabetes, and osteoporosis and neurodegenerative diseases

Polyphenols are naturally occurring compounds found largely in the fruits, vegetables, cereals and beverages. Fruits like grapes, apple, pear, cherries and berries contains up to 200–300 mg polyphenols per 100 grams fresh weight. The products manufactured from these fruits, also contain polyphenols in significant amounts.1 7Typically a glass of red wine or a cup of tea or coffee contains about 100 mg polyphenols. Cereals, dry legumes and chocolate also contribute to the polyphenolicintake.Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In food, polyphenols may contribute to the bitterness, astringency, color, flavor, odor and oxidative stability. Polyphenols and other food phenolics is the subject of increasing scientific interest because of their possible beneficial effects on human health. This review focuses on the present understanding of the biological effects of dietary polyphenols and their importance in human health and disease.

Structure and classes of polyphenols

1. Phenolic acids: Phenolic acids are found abundantly in foods and divided into two classes:derivatives of benzoic acid and derivatives of cinnamic acid. The hydroxybenzoic acid content of edible plants is generally low, with the exception of certain red fruits, black radish and onions, which can have concentrations of several tens of milligrams per kilogram fresh weight. The hydroxycinnamic acids are more common than hydroxybenzoic acids and consists chiefly of p-coumaric, caffeic, ferulic and sinapic acids.18

1. Flavonoid : Flavonoids comprise the most studied group of polyphenols. This group has a common basic structure consisting of two aromatic rings bound together by three carbon atoms that form an oxygenated heterocycle . More than 4,000 varieties of flavonoids have been identified, many of which are responsible for the attractive colours of the flowers, fruits and leaves.Based on the variation in the type of heterocycle involved, flavonoids may be divided into six subclasses: flavonols, flavones, flavanones,flavanols,anthocyaninsandisoflavones . Individual differences within each group arise from the variation in number and arrangement of the hydroxyl groups and their extent of alkylation and/or glycosylation. Quercetin, myricetin, catechins etc. are some most common flavonoids. 19

1. Stilbenes: Stilbenes contain two phenyl moieties connected by a two-carbon methylene bridge. Occurrence of stilbenes in the human diet is quite low. Most stilbenes in plants act as antifungal phytoalexins, compounds that are synthesized only in response to infection or injury. One of the best studied, naturally occurring polyphenolstilbene is resveratrol (3,4',5trihydroxystilbene), found largely in grapes. A product of grapes, red wine also contains significant amount of resveratrol.20

Stilbenes

1. Lignans: Lignans are diphenolic compounds that contain a 2,3-dibenzylbutane structure that is formed by the dimerization of two cinnamic acid residues . Several lignans, such as secoisolariciresinol, are considered to be phytoestrogens. The richest dietary source is linseed, which contains secoisolariciresinol (up to 3.7 g/kg dry weight) and low quantities of matairesinol.21

Poly phenols and human diseases

Epidemiological studies have repeatedly shown an inverse association between the risk of chronic human diseases and the consumption of polyphenolic rich diet. The phenolic groups in polyphenols can accept an electron to form relatively stable phenoxyl radicals, thereby disrupting chain oxidation reactions in cellular components. It is well established that polyphenol-rich foods and beverages may increase plasma antioxidant capacity.22This increase in the antioxidative capacity of plasma following the consumption of polyphenol-rich food may be explained either by the presence of reducing polyphenols and their metabolites in plasma, by their effects upon concentrations of other reducing agents (sparing effects of polyphenols on other endogenous antioxidants), or by their effect on the absorption of pro-oxidative food components, such as iron. Consumption of antioxidants has been associated with reduced levels of oxidative damage to lymphocytic DNA. Similar observations have been made with plyphenol-rich food and beverages indicating the protective effects of polyphenol.