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Research J. Pharm. and Tech.2 (2): April.-June. 2009,

238

ISSN 0974-3618 www.rjptonline.org

REVIEW ARTICLE

Role of Antioxidants in Common Health Diseases

Prithviraj Chakraborty*1, Suresh Kumar

1, Debarupa Dutta

2, and Vikas Gupta

1

1S.D. College of Pharmacy, Barnala, Punjab 148101

2Dept. of Pharma. Chemistry, Himalayan Pharmacy Institute, Majhitar, Rangpo, East Sikkim -737136 India

*Corresponding Author E-Mail: [email protected]

ABSTRACT:Antioxidants are intimately involved in the prevention of cellular damage - the common pathway for cancer, aging, and

variety of diseases. Several berries, fruits, nuts, seeds, vegetables, drinks and spices have been found to be high in tota

antioxidants. The body relies on obtaining its anti-oxidants from food and other supplements. Free radicals are highl

reactive molecules containing one or more unpaired electrons in their outermost shell and the only way of neutralizin

them and their harmful effects is through anti-oxidants which help in the break down of chemical reactions that caus

transfer of electrons from healthy cells into free radicals. In view of the immense medicinal importance its an effort to

compile all the information reported on its mechanism, process, defense and methods of assessing antioxidant activitieThe present review is an attempt to generate interest among the masses regarding its immense potential in preventing an

treating several common diseases.

KEY WORDS: Antioxidants, Free radicals, Superoxide dismutase (SOD), Catalase

INTRODUCTION:Cells in the human body use oxygen to breakdown

proteins and fats that give them energy. The human body

derives its energy from the utilization of nutrients and

oxygen as fuel. It also utilizes oxygen to help the immune

system, destroys foreign substances and combats diseases.

The byproduct of this and other metabolic process can

lead to development of molecular agents that react withbody tissues in a process called oxidation. This process is

a natural phenomenon of energy generation system and its

by-product called free radicals can damage healthy cells

of the body.

DEFINITION:-An antioxidant is a molecule capable of slowing or

preventing the oxidation of other molecules.In a

biological system they may protect cells from damage

caused by unstable molecules known as free radicals.

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 or

polyphenols.They are believed to play a role in preventing

the development of such chronic diseases as cancer, heart

disease, stroke, Alzheimer's disease, Rheumatoid arthritis,

and cataracts.

Received on 08.01.2009 Modified on 11.04.2009

Accepted on 15.05.2009 RJPT All right reservedResearch J. Pharm. and Tech.2 (2): April.-June. 2009.Page 238-244

Antioxidants help in:

Destroying the free radicals that damage cells. Promoting the growth of healthy cells. Protecting cells against premature, abnormal ageing. Help fight age-related macular degeneration. Provide excellent support for the bodys immune

system.

Research on the role of antioxidants in biology focused ontheir use in preventing the oxidation of unsaturated fats

which is the cause of rancidity. Antioxidant activity could

be measured simply by placing the fat in the closed

container with oxygen and measuring the rate of oxygen

consumption.

CLASSIFICATION1:

Enzymatic antioxidants: -1. Primary antioxidants e.g.-SOD, Catalase, Glutathione

peroxidase.

2. Secondary enzymes e.g. - Glutathione reductaseGlucose 6-phosphate dehydrogenase.

Non-Enzymatic antioxidants:-1. Minerals e.g.-Zinc, Selenium2. Vitamins e.g.-Vitamin A, Vitamin C, Vitamin E

Vitamin F

3. Carotenoids e.g.--carotene, Lycopene, LuteinZeaxanthin

4. Low molecular weight Antioxidants e.g.-glutathioneuric acid

5. Organosulfur compounds e.g-Allium, Allyl sulfideindoles

6. Antioxidant cofactors e.g.- Coenzyme O107. Polyphenols

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Flavonoids- Xanthones- e.g.- Mangostin Flavonoids- e.g.- Quercein, Kaempferol Flavanols- e.g.- Catechin, EGCG Flavanones- e.g.- Hesperitin Flavones- e.g.- Chrysin Isoflavanoids- e.g.- Genistein Anthocyanidins- e.g.-Cyanidin, Pelagonidin

Phenolic Acid- Hydroxycinnamic acids- e.g.- Ferulic, p-coumaric Hydroxybenzoic acid e.g.- Gallic acid, Ellagic acid Gingerol CurcuminFOOD SOURCES OF ANTIOXIDANTS

2, 3, 4, 5

MECHANISM OF ANTIOXIDANTS:-Free radicals are highly reactive molecules or chemical

species containing one or more unpaired electrons in their

outermost shell. They react quickly with nearest stable

molecule to capture the electron, in need to gain stability.

They promote beneficial oxidation that produces energy

and kill bacterial invaders. If free radicals are atreasonable levels, the human body produces enzymes to

combat them and is helpful in immune system and anti

bacterial cell activity.

A single free radical can cause damage to millions of

other molecules in the body from functioning properly.

This molecular destruction is continually occurring in our

body. Although antioxidants are a result of breathing but

these free radicals attack us from many different sources

every day. They are: Alcohol, Tobacco, Dugs, Smoked

and Barbecued Foods, Harmful Chemicals and Pesticides,

and Food Additives.

GENERATION OF FREE RADICALS:

The living cell during several metabolic pathways

generates reactive oxygen species (ROS) and reactive

nitrogen species (RNS). Pathophysiological conditions

enhance the generation of ROS and RNS and lead to

oxidative stress. The generation of ROS begins with the

rapid uptake of oxygen and activation of NADPH oxidase

and the production of the super oxide free radical (O2).

2O2 + NADPH2O2 +NADP+H

ROS can also be generated through

Fenton reaction- H2O2 +Fe++Fe

++++OH +OH

Haber-Weiss reaction7- H2O2 +O2O2 +OH +OH

The free radical nitric oxide (NO), also called

endothelium-derived relaxation factor (EDRF), is formed

from arginine by nitric oxide synthase (NOS)2.

L-arg + O2 +NADPHNO + Citrulline

NO +O2ONOO8, 9 (

Peroxynitrite)

Peroxynitrite is a very strong oxidant, which reacts with

aromatic amino acid residues to form nitrotyrosine, which

can lead to enzyme inactivation. To escape ROS, RNSand lipid peroxidation dependence injury; biological

structures have protective machinery in the form of

endogenous antioxidants.

ANTIOXIDANT DEFENSE:Antioxidant defense system (ADS) against oxidative

stress is composed of several lines and antioxidants are

classified into four categories based on their function.10

FIRST: - Preventive antioxidants which suppress

formation of free radicals.

SECOND: - Radical scavenging antioxidants whichsuppress chain initiation and breaking chain propagation

reactions.

THIRD: - Repair and de novo antioxidants.

FOURTH: - Adaption where the signal for the

production and actions of free radicals induces formation

and transport of the appropriate antioxidant to the right

site.

THE ANTIOXIDANT PROCESS:Antioxidants block the process of oxidation by

neutralizing free radicals. In doing so, the antioxidantsthemselves become oxidized.

The two ways by which they act are-

Chain-breaking - When a free radical releases orsteals an electron, a second radical is formed. This

molecule then turns around and does the same thing

to a third molecule, continuing to generate more

unstable products. The process continues unti

termination occurs - either the radical is stabilized by

a chain-breaking antioxidant such as beta-carotene

and vitamins C and E, or it simply decays into a

harmless product.

Preventive - Antioxidant enzymes like superoxidedismutase, catalase and glutathione peroxidase

prevent oxidation by reducing the rate of chain

initiation. They can also prevent oxidation by

stabilizing transition metal radicals such as copper

and iron.

ENZYMATIC ANTIOXIDANTS:The antioxidant enzymes superoxide dismutase (SOD)

catalase (CAT) and glutathione peroxidase (GPx)

glutathione reductase, thioredoxin reductase, heme

Vitamin C Fruits (especially citrus) and vegetables,including green and red peppers, tomatoes,potatoes, and green, leafy varieties (eg,

spinach and collard greens).

Vitamin E Vegetable oils (eg, soybean, corn, andsafflower) and vegetable oil products (eg,

margarine), whole grains, wheat germ, nutsand seeds, and green, leafy vegetables.

b-Carotene Yellow-orange fruits (eg, cantaloupe) andvegetables (eg, carrots) and green, leafy

vegetables.

Polyphenolic

antioxidants

Tea, coffee, soy, fruit, olive oil, chocolate,cinnamon, oregano and red wine.6

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oxygenase and biliverdin reductase serve as primary line

of defense in destroying free radicals.

CATALASE:An enzyme found in the blood and in most living cells

that catalyzes the decomposition of hydrogen peroxide

into water and oxygen.

Catalase is a common enzyme found in living organisms.

Its functions include catalyzing the decomposition ofhydrogen peroxide to water and oxygen. Catalase has one

of the highest turnover rates of all enzymes; one molecule

of catalase can convert millions of molecules of hydrogen

peroxide to water and oxygen per second.

Catalase is a tetramer of four polypeptide chains, each

over 500 amino acids long. It contains four porphyrin

heme groups which allow the enzyme to react with the

hydrogen peroxide. The optimum pH for catalase is

approximately neutral (pH 7.0), while the optimum

temperature varies by species.

Haem-containing catalase breaks down hydrogenperoxide by a two-stage mechanism in which hydrogen

peroxide alternately oxidises and reduces the haem iron at

the active site.

In the first step, one hydrogen peroxide molecule oxidises

the haem to an oxyferryl species.

In the second step, a second hydrogen peroxide molecule

is used as a reductant to regenerate the enzyme, producing

water and oxygen.

Some catalase contains NADPH as a cofactor, which

functions to prevent the formation of an inactivecompound. Catalases may have another role: the

generation of ROS, possibly hydro peroxides, upon UVB

irradiation. In this way, UVB light can be detoxified

through the generation of hydrogen peroxide, which can

then be degraded by the catalase. NADPH may play a

role in providing the electrons needed to reduce molecular

oxygen in the production of ROS.

Much of the hydrogen peroxide that is produced during

oxidative cellular metabolism comes from the breakdown

of one of the most damaging ROS, namely the superoxide

anion radical (O2-). Superoxide is broken down by

superoxide dismutase into hydrogen peroxide and oxygen.

Superoxide is so damaging to cells that mutations in thesuperoxide dismutase enzyme can lead to ALS, which is

characterised by the loss of motoneurons in the spinal

cord and brain stem, possibly involving the activation of

caspase-12 and the apoptosis cascade via oxidative stress.

The reaction of catalase in the decomposition of

hydrogen peroxide is:2 H2O2 2 H2O + O2

SUPEROXIDE DIMUTASE:Superoxide dismutase (SOD) is an enzyme that removes

the superoxide (O2-) radical, repairs cells and reduces the

damage done to them by superoxide, the most common

free radical in the body. SOD is found in both the dermis

and the epidermis, and is key to the production of healthy

fibroblasts (skin-building cells).

2 H2O2 2 H2O + O2

Superoxide Dismutase (SOD) catalyzes the reduction ofsuperoxide anions to hydrogen peroxide. It plays a critica

role in the defense of cells against the toxic effects of

oxygen radicals. SOD competes with nitric oxide (NO)

for superoxide anion, which inactivates NO to form

peroxynitrite. Therefore, by scavenging superoxide

anions, SOD promotes the activity of NO. SOD has

suppressed apoptosis in cultured rat ovarian follicles

neural apoptosis in neural cell lines, and transgenic mice

by preventing the conversion of NO to peroxynitrate, an

inducer of apoptosis.11,12,13

Covalent conjugation of

superoxide dismutase with polyethylene glycol (PEG) has

been found to increase the circulatory half-life and

provides prolonged protection from partially reducedoxygen species.

14

The SOD-catalyzed dismutation of superoxide may be

written with the following half-reactions:

M(n+1) +

SOD + O2M

n+ SOD + O2

Mn+

SOD + O2

+ 2H+M

(n+1) + SOD + H2O2. ,

Where M = Cu (n=1)

Mn (n=2), Fe (n=2) , Ni (n=2)

In this reaction the oxidation state of the metal cations

oscillates between n and n+1.

SUPEROXIDE DIMUTASE REACTION:Superoxide Dismutase

O2-

O2Superoxide Dismutase

O2 + 2 H+

H

Km for O2- for bovine SOD = 0.35 Mm

GLUTATHIONE PEROXIDASES (GSHPx):They are a group of selenium dependent enzymes. Four of

its isoforms include

Cytosolic GSHPx1

Plasma GSHPx

Phospholipid hydroperoxide PHGSHPx

Gastrointestinal GSHPx-GI

All GSHPx require GSH as cofactor and secondaryenzymes, such as glutathione reductase and glucose-6

phosphate dehydrogenase for proper functioning. G-6

PDH generates NADPH to recycle the GSH.

2GSH+H2O2GSSG+2H2O

NON ENZYMATIC ANTIOXIDANTS:

They are classified into two groups:

Endogenous antioxidants Exogenous antioxidants

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The major extracellular endogenous antioxidants found in

human plasma are the transition metal binding proteins

i.e. ceruloplasmin, transferrin, hepatoglobin and albumin.

They bind with transition metals and control the

production of metal catalyzed free radicals. Albumin and

ceruloplasmin are the copper ions sequesters.

Hepatoglobin binds with hemoglobin, ferritin and

transferrin with free iron. Lipoic and uric acids, bilirubin,

ubiquinone and glutathione are non protein endogenous

antioxidants which inhibit the oxidation processes byscavenging free radicals.

SOME COMMON ANTIOXIDANTS:There are a hundreds of antioxidants of natural and

synthetic origin. The interest of such compounds is due to

their effective role against the destructive actions of free

radicals. Some common antioxidants are as follows:

VITAMIN E:It is the most common naturally occurring antioxidant. It

has a phytyl chain which is attached to its chromanol

nucleus.

ASCORBIC ACID (VITAMIN C):It is a water soluble electron donar vitamin. It donates two

electrons from C-2 and C-3 double bond carbons to act as

an antioxidant which results in the formation of an

intermediate free radical, semi dehydroascorbic acid E.

The resulting ascorbate free radicals reduce to a neutral

ascorbate molecule.

CAROTENOIDS:They are a large group of compounds with the basic

skeleton of a polyisoprenoid carbon chain with a no. of

conjugated double bonds.

MELANINS AS ANTIOXIDANTS:Melanin pigments are large polymers synthesized from

amino acids that have strong light-absorbing capabilities

across the ultravioletvisible spectrum18. They occur in

two main forms:

(1) Eumelanin, which confers black and grey colours,

(2) Phaeomelanin, which bestows chestnut and buff

colours.

Animals like mosquitofish, Gambusia holbrooki15

,

house sparrows, Passer domesticus16

, fence lizards,

Sceloporusundulatus17

, and African lions, Pantheraleo18

all use melanins as display pigments in feathers, scales,

or hair to attract mates or to repel rivals19

. Among the

many potential physiological functions of melanins20,which include tissue strengthening

21, photo protection

22

and thermoregulation23

, is their role as antioxidants and

immunostimulants24, 25

. As molecules that contain both

oxidizing (o-quinone) and reducing (o-hydroquinone)

functional groups, both eu- and phaeomelanin have the

ability to quench potentially damaging reactive oxygen or

nitrogen species (e.g. singlet oxygen, hydroxyl or peroxyl

radical, superoxide anion) via either electron donation or

capture26

. Melanins have been touted as valuable free-

radical scavengers in several organisms, including fungi27

,

amphibians28

and humans26, 29, 30

. The dermal and

epidermal tissues (e.g. skin, retina) of animals are often

heavily melanized, and most have speculated that this is

to protect individuals from harmful solar UVrays31

.

Melanin is an integral component of the immune

responses of many invertebrates32

, and there are severa

mechanisms and lines of evidence linking melanins and

immunity in vertebrates (e.g. phagocytosis, lysosoma

enzyme activity, cytokine regulation, nitric oxideproduction)

33. The ability of melanins to bind and

sequester toxic metals may be yet another line of

physiological defence against oxidative stress in

animals17

.

PTERINS AS ANTIOXIDANTS:Pterin pigments are a group of nitrogenous, heterocyclic

compounds that are catabolic by-products of purines

They occur as red, orange and yellow pigments, which

orange sulphur butterflies, Colias eurytheme34

, guppies

Poecilia reticulata35

and green anoles, Anolis sp.36

, as

well as many other insects, fish, amphibians and reptiles

incorporate into their sexual colour displays.

Pterins have also been identified in the colorful red

orange and yellow eyes of birds such as starlings

blackbirds, owls and pigeons37

. Like melanins, pterins

can also be synthesized by non integumentary tissues

mostly by immune cells (e.g. monocytes, macrophages)38

. Activation of the immune system (e.g. by lymphokines

like gamma interferon) is known to stimulate the release

of pterins (such as neopterin and 7, 8-dihydroneopterin)

from primate macrophages and monocytes39

. The role of

pterins as immune cell protectants is so robust that their

concentrations in serum and urine are used as clinica

biomarkers for immune performance in humans (e.gallograft rejection, autoimmune disease

viral/bacterial/parasitic infections)40, 41

.

Certain pterins, like tetrahydrobiopterin, are also known

to modulate receptor binding affinity of interleukin 2

which is an integral part of the T-cell-mediated immune

response42

.

PORPHYRINS AS ANTIOXIDANTS:Porphyrins are generally united by their heterocyclic

pyrrolic molecular structure but often divided by the type

of metal ion found at the core of the super-ring. The most

familiar representatives include chlorophyll as well as

haem43, which colours the fleshy, blood-engorged redparts of many birds

44, 45. A different set of porphyrins has

been classified from the eggshells and feathers of birds

(reviewed in With 1973, 1978). Most if not all porphyrins

which include reddish-brown coproporphyrin and

uroporphyrin in the feathers of goatsuckers, bustards and

owls46

and protoporphyrin and biliverdin (a bile pigment)

in brown and blue eggs, respectively47, 48

, are derivatives

of haem from erythrocytes.

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One of the earliest pigments described from bird feathers

was the uroporphyrin-copper complex known as turacin

in the red feathers of turacos49

. Recent work has

emphasized the radical-trapping abilities of some of the

porphyrins and porphyrin-derivatives found in birds, such

as protoporphyrin50, 51, 52

and biliverdin53, 54

. Haem55

and

hemoglobin56, 57

themselves have been touted as potent

antioxidants.

PSITTACOFULVINS AS ANTIOXIDANTS:For over a century, ornithologists have known that parrots

use an unusual class of pigments to colour their plumage

red, orange and yellow. It was only recently, however,

that the biochemical structure of these compounds was

elucidated 58. A larger survey of red feather pigments in

parrots uncovered the same set of polyenes in 45 species

spanning the three main parrot families59

, including

species with sexually dichromatic plumage (e.g. Eclectus

parrot, Eclectus roratus). These noncarotenoid

lipochromes apparently are found in nature only in parrot

feathers. To date, only a single study has been conducted

on the antioxidant action of psittacofulvins. Morelli58

etal. used electron paramagnetic resonance to investigate

the ability of these colorful molecules to quench free

radicals in vitro. They found that these pigments can act

as potent antioxidants, exhibiting strong inhibition of

hydroxyl (OH) radical formation.

FLAVONOIDS AS ANTIOXIDANTS:Blue butterflies from the family Lycaenidae acquire blue

and UV hues on their wings for the presence of

flavonoids.60

Flavonoids, include the anthocyanins,

flavonols, flavones and flavanones, are one of the primary

classes of colorants in plants, bestowing bright colours on

flowers, fruits and berries

61

. These butterflies acquirehost plant flavonoids as larvae and sequester these in

wing scales as adults. In the common blue butterfly,

Polyommatus icarus, males show strong mate preferences

for flavonoid-rich, highly UV-reflective females60

.

Flavonoids also exist as valuable antioxidants in plant

foods. There is abundant evidence from in vitro

biochemical studies that flavonoids defend cells from

lipid peroxidation62, 63

, and from human intervention

studies that dietary supplements decrease incidence of

cancer and atherosclerosis. Quercetin is also the flavonoid

stored in the wings ofP. icarus60

.

METHODS OF ASSESSSING ANTIOXIDANT

ACTIVITY OF PLANT EXTRACTS:The antioxidant activity of a compound or extract can be

studied by 1,1-Diphenyl-1,2-picrylhydrazyl(DPPH)

assay,64

Thiobarbituric acid reactive substances(TBARS)

assay,65

Superoxide dismutase(SOD),66

Assay of

catalase(CAT),66

Glutathione peroxide(GPX) activity,67

Xanthine oxidase(XO) activity,68

Deoxyribose

degradation assay,69

Reduced Glutathione(GSH).70

All

these methods can be done either in vitro or in vivo.

Among all the methods, DPPH is very rapid, simple,

sensitive, and reproducible for the screening of large

number of plant extracts.71

Antioxidant herbal formulations available in the marker

are Brahma rasayana, Geriforte, Abana and HD-3, MAK-

4 and Reatival.

EFFECTS OF DIETARY ANTIOXIDANTS ON

CLINICAL OUTCOMES:Recent studies have suggested that antioxidants may

affect clinical outcomes. The Indian Experiment of Infarct

Survival Study72

tested the therapeutic efficacy of

antioxidants in reducing post-MI complications, many of

which are proposed to result from oxidative reperfusion

injury. Infarct size and angina and total cardiac events

were significantly reduced in individuals receiving

antioxidants in the post-MI period. Another potentia

therapeutic role for antioxidants is in the reduction of

restenosis after angioplasty. This role has been addressed

in several recent trials.73,74

The Multivitamins and

Probucol (MVP) Study tested the effects of a combination

of vitamin C (1000 mg/d), vitamin E (1400 IU/d), and b-carotene (100 mg/d); probucol (a lipid-lowering drug with

antioxidant effects; 1000 mg/d); the dietary antioxidants

plus probucol (in the same amounts); or placebo alone on

the rate and severity of restenosis.73

The Probuco

Angioplasty Restenosis Trial (PART) compared probuco

(1000 mg/d) with placebo.74

In both studies, treatments

were initiated 1 month before and maintained for 6

months after elective angioplasty. Probucol significantly

reduced restenosis due to its antioxidant properties. In the

MVP study, similar results were not observed for the

dietary antioxidants, which had no effect alone and

appeared to negate the beneficial effects of probucol when

given in combination.

73

Beneficial effects have beenobserved for vitamins C and E in other studies75,76,

Because the long-term use of probucol in diseased

individuals is of concern, owing to adverse effects on

plasma high-density lipoprotein levels (a 41% reduction

was noted in the MVP study), dietary antioxidants, could

represent a good alternative.

CONCLUSION:Antioxidants are emerging as prophylactic and therapeutic

agents. Several antioxidants have been found to be

pharmacologically active as prophylactic and therapeutic

agents for several diseases. These agents are used as

nutritional supplements for prophylaxis of certain diseases

along with mainstream therapy. Bioavailability of dietaryantioxidants is dependant on a number of factors such as

poor solubility, inefficient permeability instability and

extensive first pass metabolism before reaching the

systemic circulation and GI degradation. There is need to

develop new drug delivery systems to improve the

performance of antioxidants.

Along with the evidence of positive benefits, there are

several reports regarding the negative effects of

antioxidants use, especially concerning dietary

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supplementation with Vitamin C and E, beta-carotene and

selenium. Of primary concern are the potentially

deleterious effects of antioxidant supplements on ROS

levels, esp. when precise modulation of ROS levels are

needed to allow normal cell function or to promote

apoptotic cell death of precancerous transformed cells.

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