INTRODUCTION:
Cells in the
human body use oxygen to breakdown the proteins and fats that give them energy.
The human body lead to development of molecular agents that react with body
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.1 Oxygen is essential element for life.
Oxidative properties of oxygen play a vital role in diverse biological
phenomena. Oxygen has double-edged properties, being essential for life; it can
also aggravate the damage within the cell by oxidative events.2 Free
radicals and its adverse effects were discovered in the last decade. Free
radicals are responsible for causing a wide number of health problems which
include cancer, aging, heart diseases and gastric problems etc.3 The
byproduct of this and other metabolic process can lead to development of
molecular agents that react with body 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.
ANTIOXIDANTS:
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 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. The human
body naturally produces antioxidants but the process is not 100 percent
effective in case of overwhelming production of free radicals and that
effectiveness also declines with age. Increased intake of antioxidants can
prevent diseases and lower the health problems. Foods may possibly enhance
antioxidant levels because they contain a lot of antioxidant substances. Fruits
and vegetables are rich in key antioxidants such as vitamin A, C, E,
beta-carotene and important minerals, including selenium and zinc. Natural
products, mainly obtained from dietary sources provide a large number of
antioxidants.4
CLASSIFICATION:5
Enzymatic antioxidants:
1 Primary
antioxidants e.g.-SOD, Catalase, Glutathione peroxidase.
2 Secondary
enzymes e.g. - Glutathione reductase, Glucose 6-phosphate dehydrogenase.
Non-Enzymatic antioxidants:
1 Minerals e.g.-Zinc, Selenium
2 Vitamins e.g.-Vitamin A,
Vitamin C, Vitamin E,
3 Carotenoids e.g.--carotene,
Lycopene, Lutein, Zeaxanthin
4 Low molecular weight
Antioxidants e.g.-glutathione, uric acid
5 Organosulfur compounds e.g- Allium,
Allyl sulfide, indoles
6 Antioxidant cofactors e.g.-
Coenzyme O10
7 Polyphenols –
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
·
Curcumin
SOURCES OF FREE RADICALS:
Free radicals
and other reactive oxygen species (ROS) 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
chemicals6,7. The sources include endogenous production from
mitochondria9, microsomes10, enzymes or enzymatic
reactions89 phagocytes 10 and metal ions 11,12 .
Exogenous sources of free radicals include cigarette smoke 13,14
alcoholism 15 toxins and
drugs 16 17 and ionizing radiation.
|
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, and safflower) and vegetable oil products (eg,
margarine), whole grains, wheat germ, nuts and seeds, and green, leafy
vegetables.
|
|
b-Carotene
|
Yellow-orange
fruits (eg, cantaloupe) and vegetables (eg, carrots) and green, leafy
vegetables.
|
|
Polyphenolic
antioxidants
|
Tea, coffee, soy,
fruit, olive oil, chocolate, cinnamon, oregano and red wine 18
|
MECHANISM OF ANTIOXIDANTS:
A molecule with one or more unpaired electron in its
outer shell is called a free radical19-21. Free radicals are formed
from molecules via the breakage of a chemical bond such that each fragment
keeps one electron, by cleavage of a radical to give another radical and, also via
redox reactions 22 23. Free radicals include hydroxyl (OH•),
superoxide (O2•ˉ), nitric oxide (NO•), nitrogen dioxide (NO2•),
peroxyl (ROO•) and lipid peroxyl (LOO•). Also, hydrogen peroxide (H2O2),
ozone (O3), singlet oxygen (1O2), hypochlorous acid (HOC1),
nitrous acid (HNO2), peroxynitrite (ONOOˉ), dinitrogen trioxide
(N2O3), lipid peroxide (LOOH), are not free radicals and
generally called oxidants, but can easily lead to free radical reactions in
living organisms24 .
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.
ROLE IN HEALTH AND DISEASE:
Burns:
Free radical mediated cell injury has been supported
by post burn increases in systemic and tissue levels of lipid peroxidation
products such as conjugated dienes, thiobarbituric acid reaction products, or
malondialdehyde (MDA) levels. Antioxidant therapy in burn (glutathione, N-
acetyl-L-cysteine, or vitamins A, E, and C alone or in combination) have been
shown to reduce burn and burn/sepsis mediated mortality, to protect
microvascular circulation, reduce tissue lipid peroxidation, improve cardiac
output, and to reduce the volume of required fluid resuscitation 25.
Ageing:
One of the most popular theories of aging is the
"Free Radical Theory of Aging." This theory was first proposed by Dr.
Denham Harman 26, and postulates that aging results from an
accumulation of changes caused by reactions in the body initiated by highly
reactive molecules known as "free radicals."
Cancer:
The development of cancer in humans is a complex
process including cellular and molecular changes mediated by diverse endogenous
and exogenous stimuli. It is well established that oxidative DNA damage is
responsible for cancer development.27-29. Since oxidative stress is
generally perceived as one of the major causes for the accumulation of
mutations in the genome, antioxidants are believed to provide protection
against cancer30. Fortunately, certain antioxidant supplements like
vitamins C and E can prevent much oxidative damage to DNA and thus reduce the
ability of the oxidants to induce cancer31. Supplementing cancer
patients with adjuvant therapy of resveratrol (a flavonoid) may have some
benefit for a more successful radiotherapy32.
Cardiovascular diseases:
Oxidative damage and the production of free radicals
in the endothelium are two of the main factors involved in the pathogenesis of
the atherosclerotic process that causes CVD. Research concerning nutritional
regimens has shown that persons who consume large amounts of fruit and
vegetables have lower incidences of cardiovascular diseases, stroke, and
tumors, although the precise mechanisms for this protective effect are elusive.
Possible explanations include (a) increased consumption of dietary fiber, (b)
reduced consumption of dietary cholesterol and other lipids, and (c) increased
intake of the antioxidant vitamins (A, C, and E)33,34. Many studies
showed that vitamin E intake over an extended period was associated with
decreased risk of cardiovascular events35. Tea and wine, rich in
flavonoids, seem to have beneficial effects on multiple mechanisms involved in
atherosclerosis.36
Repercussion Injury:
Reperfusion injury is defined as the damage to cells
which occurs following restoration of the blood and oxygen supply to the tissue
after a period of ischemia. Antioxidants are able to prevent or reduce the
severity of this type of tissue damage37. Bhakuni P et al in their
study found that oxidative stress parameters in the post reperfusion patients
were restored back to normal or near normal levels by supplementation with
vitamin C. 38
Hypertension:
Increased oxidative stress in hypertensive patients
reduces activity of SOD39. Vitamin E supplementation provides
protection against oxidative stress by restoring the enzyme activity and
preventing further damage caused by lipid peroxidation.
Diabetes:
Under conditions of hyperglycemia, excessive amounts
of superoxide radicals are produced inside vascular cells and this can interfere
with NO production leading to the possible complications40. It is
found that dietary GSH suppresses oxidative stress in vivo in prevention of
diabetic complications such as diabetic nephropathy and neuropathy41.
Cataract:
Under the action of free radicals, the crystalline
proteins in the lens can cross-link and aggregate, leading to the formation of
cataracts42. H2O2 is the major oxidant
involved in cataract formation43. The young lens has substantial
reserves of antioxidants to prevent lens damage and proteolytic enzymes,
proteases that selectively remove damaged
proteins. Compromises of function of the lens with aging are associated
and may be causally related to depleted
antioxidant reserves, diminished antioxidant enzyme capabilities
and decreased proteases44 .
Chronic high dose intake of lutein has improved visual
acuity in small numbers of subjects with age-related cataract45.
Pro-drug antioxidant N-acetylcarnosine, which is acetyl derivative of the
natural dipeptide antioxidant L-carnosine found in meat has shown promising
results in the prevention of cataract46.
Inflammatory diseases:
In inflammation neutrophils and macrophages by virtue
of antibacterial killing mechanisms
generate superoxide, H2O2, and hypochlorite resulting in activation of
proteases and tissue damage. Antioxidant therapy such as green tea polyphenols
and gene therapy with superoxide dismutase has a markedly attenuated disease47.
Giving antox (specially formulated nutritional supplement) which contains
the antioxidants selenium, betacarotene, L-methionine, and
vitamins C and E improves the quality of life and reduces pain in patients
suffering from chronic pancreatitis48.
Rheumatoid Arthritis:
Rheumatoid arthritis is an autoimmune disease
characterized by chronic inflammation of the joints and tissue around the
joints with infiltration of macrophages and activated T cells49,50. The
pathogenesis of this disease is due to the generation of ROS and RNS at the
site of inflammation. Oxidative damage and inflammation in various rheumatic
diseases were proved by increased levels of isoprostanes and prostaglandins in
serum and synovial fluid compared to controls. There is necessity for
therapeutic co-administration of
antioxidants along with conventional drugs to such patients51.
Neurological diseases:
Oxidative stress has been investigated in neurological
diseases including Alzheimer’s disease, Parkinson’s disease, multiple
sclerosis, amyotrophic lateral sclerosis (ALS), memory loss, depression52,53.
In a disease such as Alzheimer’s, numerous experimental and clinical studies
have demonstrated that oxidative damage plays a key role in the loss of neurons
and the progression to dementia54. The production of ß-amyloid, a
toxic peptide often found present in Alzheimer’s patients’ brain, is due to
oxidative stress and plays an important role in the neuro degenerative
processes55. Antioxidant supplementation play an important role in
controlling oxidative stress and decreasing disease activity in these patients.
AIDS:
Oxidative stress may contribute to several aspects of
HIV disease. For this reason, the exogenous supply of antioxidants, as natural
compounds (vitamin A, C, E, Se and Zinc) and new-generation antioxidants
(cyclodecan-9-yl- xanthogenate (D609), GPI 104, Memantine) that scavenge free
radicals might represent an important additional strategy for the treatment of
HIV infection in the era after HAART therapy has been applied56 .
Infertility:
Increased lipid peroxidation of the plasma membrane of
sperms caused by ROS is damaging to the sperms57. Recently the role
of L-carnitine and L-acetyl carnitine in scavenging the free radicals and
protecting the cell membrane has gained much importance in treatment of male
infertility58 Vitamin E, a major chain breaking antioxidant in the
sperm membrane appears to have dose dependent effect. Administration of 100mg
of vitamin E thrice daily for six months in a group of asthenozoospermic
patients with normal female partner has been found to cause a significant
decrease in lipid peroxidation and increase in motility59.
CONCLUSION:
The implication of oxidative stress in the etiology of
several chronic and degenerative diseases suggests that antioxidant therapy
represents a promising avenue for treatment. 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. Along with the evidence of
positive benefits, there are several reports regarding the negative effects of
antioxidants use, especially concerning
dietary supplementation with Vitamin C and E, beta-carotene and
selenium. Further research is needed before this supplementation could be
officially recommended as an adjuvant therapy.
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