Free radicals and antioxidants in health and disease

Volume 4, Issue 2, 1998, Page 350-360

K. Bagchi and S. Puri
Introduction
It is ironic that oxygen, an element indispensable for life can, under certain situations, have severely
deleterious effects on the human body. Most of the potentially harmful effects of oxygen are due to the
formation and activity of a number of chemical compounds, known as reactive oxygen species, which
have a tendency to donate oxygen to other substances. Many such reactive species are free radicals and
have a surplus of one or more free-floating electrons rather than having matched pairs and are, therefore,
unstable and highly reactive. Types of free radicals include the hydroxyl radical (OH.), the superoxide
radical (O.2), the nitric oxide radical (NO.) and the lipid peroxyl radical (LOO.).
Production of free radicals in the human body
Free radicals and other reactive oxygen species 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 (Figure 1). Enzymatic reactions which
serve as sources of free radicals include those involved in the respiratory chain, in phagocytosis, in
prostaglandin synthesis and in the cytochrome P450 system. Free radicals also arise in non-enzymatic
reactions of oxygen with organic compounds as well as those initiated by ionizing radiations. Some
internally generated sources of free radicals are [1]:

mitochondria

phagocytes

xanthine oxidase

reactions involving iron and other transition metals

arachidonate pathways

peroxisomes

exercise

inflammation

ischaemia/reperfusion.

Some externally generated sources of free radicals are [1]:

cigarette smoke

environmental pollutants

radiation

ultraviolet light

certain drugs, pesticides, anaesthetics and industrial solvents

ozone.

With electrons unhinged, free radicals roam the body, wreaking havoc. The free radical, in an effort to
achieve stability, at
tacks nearby molecules to obtain another electron and, in doing so, damages those molecules. This
situation can be compared to letting a bachelor into a dance where people have come as couples. The
bachelor begins cutting in, each time leaving another bachelor, so the breaking up of couples spreads
through the dance floor.
If free radicals are not inactivated, their chemical reactivity can damage all cellular macromolecules
including proteins, carbohydrates, lipids and nucleic acids (Figure 2). Their destructive effects on proteins
may play a role in the causation of cataracts. Free radical damage to DNA is also implicated in the
causation of cancer and its effect on LDL cholesterol is very likely responsible for heart disease. In fact,
the theory associating free radicals with the aging process has also gained widespread acceptance (see
Box 1).
The free radical diseases
A well accepted fact is the increasing incidence of disease with advancing age. A plausible explanation for
the association of age and disease is based on the implication of free radical reactions in the
pathogenesis of several disorders.
Free radical reactions are expected to produce progressive adverse changes that accumulate with age
throughout the body. Such "normal" changes with age are relatively common to all. However,
superimposed on this common pattern are patterns influenced by genetics and environmental differences
that modulate free radical damage. These are manifested as diseases at certain ages determined by
genetic and environmental factors. Cancer and atherosclerosis, two major causes of death, are salient
"free radical" diseases. Cancer initiation and promotion is associated with chromosomal defects and
oncogene activation. It is possible that endogenous free radical reactions, like those initiated by ionizing
radiation, may result in tumour formation. The highly significant correlation between consumption of fats
and oils and death rates from leukaemia and malignant neoplasia of the breast, ovaries and rectum
among persons over 55 years may be a reflection of greater lipid peroxidation [2]. Studies on
atherosclerosis reveal the probability that the disease may be due to free radical reactions involving dietderived lipids in the arterial wall and serum to yield peroxides and other substances. These com
pounds induce endothelial cell injury and produce changes in the arterial walls [3].
Free radicals, however, are not always harmful. They also serve useful purposes in the human body.
Several observations indicate that the oxygen radicals in living systems are probably necessary
compounds in the maturation processes of cellular structures. Furthermore, white blood cells release free

radicals to destroy invading pathogenic microbes as part of the body's defence mechanism against
disease. Hence, the complete elimination of these radicals would not only be impossible, but also harmful.
Counteracting free radical damage
The human body has several mechanisms to counteract damage by free radicals and other reactive
oxygen species. These act on different oxidants as well as in different cellular compartments.
One important line of defence is a system of enzymes, including glutathione peroxidases, superoxide
dismutases and catalase, which decrease concentrations of the most harmful oxidants in the tissues.
Several essential minerals including selenium, copper, manganese and zinc are necessary for the
formation or activity of these enzymes. Hence, if the nutritional supply of these minerals is inadequate,
enzymatic defences against free radicals may be impaired.
The second line of defence against free radical damage is the presence of antioxidants. 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. Some such antioxidants, including glutathione, ubiquinol and uric acid,
are produced during normal metabolism in the body. Other lighter antioxidants are found in the diet.
Although about 4000 antioxidants have been identified, the best known are vitamin E, vitamin C and the
carotenoids. Many other non-nutrient food substances, generally phenolic or polyphenolic compounds,
display antioxidant properties and, thus, may be important for health.
Although a wide variety of antioxidants in foods contribute to disease prevention, the bulk of research has
focused on three antioxidants which are essential nutrients or precursors of nutrients. These are vitamin
E, vitamin C and the carotenoids. Each of these antioxidant nutrients have specific activities and they
often work synergistically to enhance the overall antioxidant capability of the body (Table 1).
The balance between the production of free radicals and the antioxidant defences in the body has
important health implications. If there are too many free radicals produced and too few antioxidants, a
condition of "oxidative stress" develops which may cause chronic damage. As mentioned above, free
radicals have been implicated in several health problems. Cancer, atherosclerosis, cerebrovascular
accidents, myocardial infarction, senile cataracts, acute respiratory distress syndrome and rheumatoid
arthritis are just a few examples. Numerous studies have shown the protective effects of antioxidant
nutrients on these health problems.
Vitamin E is the collective name for eight compounds, four tocopherols and four tocotrienols, found in
nature. It is a fat-soluble substance present in all cellular membranes and is mainly stored in adipose
tissue, the liver and muscle. Vitamin E is a principal antioxidant in the body and protects polyunsaturated
fatty acids in cell membranes from peroxidation. It is a singlet oxygen quencher, neutralizing these highly
reactive and unstable singlet oxygen molecules. In fact, singlet oxygen can damage DNA and be
mutagenic. Vitamin E also protects the double bonds of b-carotene from oxidation and thus exhibits a
sparing effect. Due to the ability of vitamin E to work at higher oxygen pressures, free radicals are
scavenged and tissue injury is minimized. Besides its anti-aging properties, vitamin E is known to afford
protection against cancer, ischaemia and reperfusion injury, cataract, arthritis and certain neurological
disorders.
Vitamin E and cancer
Cancer is the culmination of a multistep process that occurs over a period of several years or decades.
The underlying cause is thought to be DNA damage, much of which is oxidative in nature. These oxidative
processes, the mechanisms of which are not clearly understood, occur during the promotional stage of
carcinogenesis. Hence, antioxidants may be able to cause regression of premalignant lesions or inhibit
their development into cancer.

Several functions of vitamin E are relevant in considering its role in cancer prevention and control.
Besides being a free radical scavenger, vitamin E at high intakes enhances the body's immune
responses. Vitamin E also inhibits the conversion of nitrites in the stomach to nitrosamines, which are
cancer promoters. A large multicentric case control study conducted by the US National Cancer Institute
associated the use of vitamin E supplements with a 50% reduction in oral cancer risk, while dietary
vitamin E and multi-vitamins had no significant effect [1]. However, another study demonstrated the
inverse relationships of both dietary vitamin E and vitamin E supplements with breast cancer risk [5].
Hence, further trials are necessary to substantiate the role of vitamin E in cancer prevention.
Vitamin E and cardiovascular disease
Oxidative stress may affect cardiovascular function in two ways; one involving the long-term development
of atherosclerosis and the other involving immediate damage during a heart attack or stroke. Free
radicals may contribute to atherogenesis by oxidizing low density lipoproteins (LDLs) which then damage
arterial walls. The oxidation of LDL cholesterol is suspected to occur at the initial stages of
atherosclerosis, and vitamin E has been shown to inhibit this oxidative reaction.
During an ischaemic episode, the supply of blood and oxygen to the tissues is cut off and consequently
cells begin to die. Restoration of blood flow and oxygen supply by reperfusion can prevent tissue damage.
However, harmful free radicals are generated during reperfusion and can damage tissues further. Vitamin
E intakes are associated with lowered risk of angina and mortality from ischaemic heart disease.
Another significant factor in the development of atherosclerosis and other vascular diseases is platelet
hyperaggregability. Vitamin E is known to inhibit platelet aggregation, as well as prostaglandin synthesis
which stimulates platelet aggregation. Epidemiological evidence strongly links high vitamin E intake to
reduced risk of coronary heart disease. Stephens et al. demonstrated that vitamin E treatment also
significantly reduced the risk of cardiovascular deaths as well as non-fatal myocardial infarctions [6].
The protective effects of vitamin E, however, have been witnessed at high doses, much more than can be
consumed through the normal diet. Whether vitamin E levels in normal diets are protective against heart
disease still remains to be verified. Further research is needed to confirm the role of vitamin E, as well as
to determine the optimal intake to protect against cardiovascular risk.
Vitamin E and eye disorders
Oxidative processes have been implicated in the causation of both cataracts and the age-related disorder
of the retina, maculopathy. Cataracts occur when the transparent material in the lens of the eye becomes
cloudy and opaque. Oxidation, induced mainly by exposure to ultraviolet light, is believed to be a major
cause of damage to the proteins of the lens. The oxidized protein precipitates out and causes cloudiness
of the lens. Antioxidants and antioxidant enzymes inactivate harmful free radicals and the protein-splitting
enzymes (proteases) remove the damaged portion from the lens, but the oxidative damage occurs at a
faster rate. Hence, oxidized protein may accumulate, and with time, the damage becomes irreversible.
All three of the major dietary antioxidants (vitamin C, vitamin E and carotenoids) have been associated
with decreased cataract risk through the retardation of lens opacity. These findings have been supported
by several epidemiological studies conducted in various parts of the world. Results of such studies of
nutrients and cataract, however, have not been consistent. Some studies have shown protective effects of
antioxidants against some types of cataract, but others have not [7]. Rouhiainen et al., for example,
reported that low plasma levels of vitamin E were associated with the worsening of early cortical lens
opacities [8].
Some scientific evidence suggests that excessive exposure to light, particularly blue light, is associated
with age-related macular degeneration. While vitamin E has thus far not been associated with
maculopathy, carotenoids are said to decrease the risk of this disorder.

Vitamin E and neurological disorders

The role of antioxidants in slowing the progression of certain neurological disorders has been suggested
as oxidation may be a causative factor in several disorders of the nervous system. Supplementation with
vitamin C and E might be of benefit in slowing the progression of Parkinson's disease. Further trials,
however, need to be conducted to substantiate these claims.
Vitamin E and aging
Cellular damage by active oxygen species, including damage associated with lipid peroxidation,
contributes to the pathological changes attributed to aging. Buttner and Burns reported a decrease in the
rate of free radical medicated lipid peroxidation on supplementation with vitamin E [9]. Improvement in
mental well-being of the elderly has been reported with vitamin E and selenium supplements. Vitamin E is
also associated with improvements in arthritis.
Vitamin C
Vitamin C, or ascorbic acid, is a water-soluble vitamin. This vitamin is a free radical scavenger and
interacts with free-radicals in the water compartment of cells as well as in the fluids between cells. It is
considered to be one of the most important antioxidants in extra cellular fluids. Vitamin C has a sparing
effect on vitamin E as it regenerates vitamin E from the tocopheroxyl radical after it has neutralized free
radicals. Its protective effects extend to cancer, coronary artery disease, arthritis and aging.
Vitamin C and cancer
Vitamin C is effective in protecting tissues against oxidative damage. It suppresses the formation of
carcinogens such as nitrosamines and quinones. Numerous studies have reported the protective effect of
fruit and vegetable consumption on incidence of cancer [10]. This is mainly attributed to the protective
effect of vitamin C against cancer.
Vitamin C and cardiovascular disease
A major culprit in the development of atherosclerosis is oxidized LDL. Vitamin C protects against this
oxidation. There is
also evidence that vitamin C increases HDL levels and may also lower total cholesterol in the blood, thus
reducing the risk of cardiovascular disease. While certain studies have failed to show any association
between vitamin C supplementation and coronary risk, studies among various European populations
indicate that coronary heart disease mortality is higher in those with blood vitamin C levels that are near
or in the deficient range.
Several epidemiological studies note an inverse association with vitamin C status and blood pressure.
However, further research is needed to substantiate these claims which presently appear inconsistent.
Vitamin C and cataracts
Use of vitamin C supplements has been inversely associated with cataract risk. High intake of fruits and
vegetables which are rich sources of ascorbic acid appear to be protective too. In several epidemiological
studies, cataract patients were shown to have low vitamin C and E intakes and low plasma vitamin C
levels. Smokers are known to have lower blood levels of vitamin C than non-smokers and, as smoking
induces free radical formation, they are at increased risk of developing cataracts.
Vitamin C and other diseases

Since oxidative processes are implicated in a variety of clinical disorders, antioxidants like vitamin C may
play a significant role in their risk reduction. Supplementation with vitamin C and E, for example, has been
reported to prove beneficial in Parkinson disease. Cigarette smoking is associated not only with reduced
sperm count and poor sperm quality but also with lower blood vitamin C levels. Supplementation with
vitamin C has been shown to improve sperm quality in heavy smokers. It has also been reported to
reduce oxidative damage to sperm DNA. Further research, however, needs to be undertaken to examine
the role of such antioxidants in reducing infertility in men who are heavy smokers or who are exposed to
oxidative stress from other causes.
Carotenoids
Carotenoids are a group of red, orange and yellow pigments found in plant foods, particularly fruits and
vegetables. Some carotenoids like b-carotene act as a precursor of vitamin A; others do not. b-carotene is
an effective antioxidant as it is one of the most powerful singlet oxygen quenchers. It can dissipate the
energy of singlet oxygen, thus preventing this active molecule from generating free radicals. Its other
antioxidant properties include the scavenging of free radicals. Unlike other nutrient antioxidants, bcarotene is efficient at low oxygen pressure. Besides b-carotene, other important dietary carotenoids
include a-carotene, lycopene, lutein, zeaxanthin and b-cryptoxanthin. Recent studies have confirmed that
lycopene has a powerful role as an antioxidant.
Carotenoids and cancer
The results of recent epidemiological studies have suggested that several carotenoids may be associated
with reduced cancer risk. The evidence is much stronger in the case of b-carotene. Numerous studies
have reported reduced risk of certain cancers with a high dietary intake of b-carotene. b-carotene may
alter the way cancer cells communicate with normal cells. Cancer cells multiply rapidly when growth
regulating signals from adjoining normal cells cease. Carotenoids act as "arbitrators" by enhancing the
communication between the two cells and helping the cancer cells to act more like normal cells.
Furthermore, if cancer cells receive the growth regulating signals, tumour growth may be suppressed.
Several clinical trials showed regression in precancerous lesions of the cervix and the lung as well as the
oral cavity with the administration of b-carotene. Studies by Zheng et al. [11] and Negri et al. [12] have
reported that dietary antioxidants, especially b-carotene, may be important in the prevention of stomach
and breast cancer. Whether the protective effects are attributable to the antioxidant nutrients themselves
or to other substances found in the same foods, however, needs to be verified.
A few contradictory reports have also emerged. These reveal that b-carotene supplementation does not
lower the rate of lung cancer [13,14,15]. b-carotene also does not reduce recurrence of adenomatous
polyps and skin cancer [16,17]. More definite data need to be generated in the next few years for a
clearer picture to emerge.
b-carotene and cardiovascular disease
The current evidence linking carotenoids with heart disease prevention is limited but promising. The
European Community Multicentric Study on Antioxidants, Myocardial Infarction and Breast Cancer has
shown that low b-carotene concentrations in adipose tissue were associated with a high risk of myocardial
infarction in current smokers [18].
Clinical trials conducted by Hennekens et al. on US male physicians showed no significant effects,
positive or negative, on cardiovascular diseases, cancer or mortality amongst those taking b-carotene
when compared to a placebo group [15]. These results need to be substantiated further; however, they
serve to re-emphasize the fact that there is no substitute for smoking cessation in the prevention of heart
diseases.

Like vitamins C and E, carotenoids have been associated with decreased cataract risk. Several studies
have reported an increased risk of developing cataracts for people with low blood levels of b-carotene.
While high intake of fruits and vegetables, rich sources of b-carotene and ascorbic acid, appears to be
protective, low intake is associated with increased cataract risk.
Exposure to blue light, in particular, has been implicated in the causation of age-related maculopathy.
Since carotenoids absorb blue light, they might be protective against this damage. A significantly reduced
risk of macular degeneration has been reported in individuals with high blood cartenoid levels. However,
further research is needed to determine conclusively whether carotenoids may reduce the risk of these
very prevalent eye disorders in older adults (Table 2).
Other dietary antioxidants
Dietary antioxidants other than vitamin E, vitamin C and the carotenoids may also be of significance in the
prevention of degenerative diseases and the maintenance of good health.
The role of the antioxidant minerals in the etiogenesis of cancer has been investigated and selenium is
emerging as a major prophylactic factor against cancer. Low selenium intake has also been linked to
myocardial ischaemia and atherosclerosis; however, evidence regarding selenium needs further
reinforcement.
There is now convincing evidence that foods containing antioxidants may be of major importance in
disease prevention. Garlic has been associated with blood cholesterol lowering properties, cardioprotective aspects, as well as anti-aging properties and this may be attributed to the antioxidants present
in it. Apparently, red wine is protective against heart disease and this may be due not to the alcohol
content of the wine but to its antioxidant content. In vitro, antioxidants isolated from red wine have been
found to inhibit oxidation of LDL (Table 3).
Humans require external sources of vitamins E and C and b-carotene as the body is unable to produce
these nutrients. Hence, efforts should be made to ensure optimum intake of foods rich in antioxidants.
Diets need to be improved and a greater emphasis placed on the consumption of antioxidant rich
vegetables and fruits. Authorities in several countries have recommended that at least five servings of
fruits and vegetables should be included in the diet daily. Unfortunately, most of our dietary patterns do
not lay such an emphasis on vegetables and fruits.
Dietary recommendations for the intake of vitamins E and C and b-carotene currently represent levels
suggested to prevent deficiencies in healthy populations. Until recommendations based on the disease
prevention abilities of these nutrients emerge, emphasis on promoting consumption of fruits and
vegetables may help in reducing the risk of degenerative diseases.
References
1. Langseth L. Oxidants, antioxidants and disease prevention. Belgium, International Life Science
Institute, 1996.
2. Lea AJ. Dietary factors associated with death rates from certain neoplasms in man. Lancet, 1966,
2:332-3.
3. Harman D. Role of free radicals in aging and disease. Annals of New York Academy of Sciences, 1992,
673:126-141.
4. Vitamins basics. In: Nutrition review. Switzerland, F Hoffman La Roche Ltd, 1994.

5. Ambrosone CB et al. Interaction of family history of breast cancer and dietary antioxidants with breast
cancer risk (New York, United States). Cancer causes and control, 1995, 6(5):407-15.
6. Stephens NG et al. Randomized controlled trial of vitamin E in patients with coronary heart disease:
Cambridge heart antioxidant study (CHAOS). Lancet, 1996, 347: 781-6.
7. Antioxidant vitamins newsletter. In: Nutrition review. Switzerland, F Hoffman La Roche Ltd, 1997, 1:1.
8. Rouhiainen P, Rouhiainen H, Solonen JT. Association between low plasma vitamin E concentration and
progression of early cortical lens opacities. American journal of epidemiology, 1996, 144(5): 496-500.
9. Buttner GR, Burns CP. Vitamin E slows the rate of free radical mediated lipid peroxidation in cells.
Archives of biochemistry and biophysics, 1996, 334(2):261-7.
10. Potter JD. Plant foods and cancer risk: science and tradition. Nutrition Foundation of India bulletin,
1997, 18(1):1-5.
11. Zheng W et al. Retinol antioxidant vitamins and cancer of the upper digestive tract in a prospective
cohort study of
post-menopausal women. American journal of epidemiology, 1995, 142(9):955-60.
12. Negri E et al. Intake of selected micronutrients and the risk of breast cancer. International journal of
cancer, 1996, 65(2):140-4.
13. Alpha Tocopherol, b-carotene Cancer Prevention Study Group. The effect of vitamin E and b-carotene
on the incidence of lung cancer and other cancers in male smokers. New England journal of medicine,
1994, 330:1029-35.
14. Omenn Gs et al. Effect of a combination of beta carotene and vitamin A on lung cancer and
cardiovascular disease. New England journal of medicine, 1996, 334(18):1150-5.
15. Hennekens CH et al. Lack of effect of long-term supplementation with beta carotene on the incidence
of malignant neoplasms and cardiovascular disease. New England journal of medicine, 1996,
334(18):1145-9.
16. Greenberg ER et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. New
England journal of medicine, 1994, 331:141-7.
17. Greenberg ER et al. A clinical trial of b-carotene to prevent basal cell and squamous cell cancers of
the skin. New England journal of medicine, 1990, 323:789-95.
18. Kardinaal AF et al. Antioxidants in adipose tissue and risk of myocardial in farction: the EURAMIC
study. Lancet, 1993, 342:1379-84.
19. Zs-Nagy I. A proposal for reconsideration of the role of oxygen free radicals in cell differentiation and
aging. Annals of the New York Academy of Sciences, 1992, 673:142-8.

What are free radicals?

Free radicals are an atom or group of atoms containing at least one unpaired electron. An
electron is a particle that normally occurs in pairs and is negatively charged which is a stable
arrangement.
Should an electron become unpaired, it becomes unstable, and to create balance again it will
bond with another molecule, which then sets off a whole chain reaction.
Free radicals are created in normal biochemical processes and the body can normally keep them
in check, but a problem is created when too many free radicals are present in the body for too
long a time. It is normal to have some free radicals in your body, since they do perform certain
necessary functions, yet, our modern lifestyle can lead to an excess of these free radicals being
formed.
Free radicals are generated when oxygen is used to produce energy but are also produced by
other external factors.
Conditions that promote formation of free radicals

Exercise
o

The increased amount of oxygen used during vigorous exercising

causes more free radicals to be formed, and although regular exercise
is beneficial to your general health, an increase in dietary antioxidants
may be called for.

Food additives
o

Food additives are added to improve the shelf life and stability of
processed and smoked foods, but these are not "body friendly".

Food preparation
o

Ozone
o

Modern day lifestyles and competitive job related stress is also a

contributing factor to excess free radicals circulating in your body.

Sunlight
o

People living in any metropolitan area are exposed to pollution, and if

you regularly commute in traffic jams or live near any industrial areas,
your body is exposed to even more harmful air particles, and
supplementation of antioxidants should be considered.

Stress
o

Unless your foodstuffs are totally organically grown, and pests

controlled by natural means, pesticides and herbicides are used on the
crops. Ingesting these pesticides causes more oxidative stress in the
body and should be neutralized by enough antioxidants being available
in the diet or through supplementation.

Pollution
o

When exposed to abnormal ozone levels, your normal metabolism may

not be able to cope with the extra free radicals caused.

Pesticides
o

When you are cooking food it may increase the amount of free radicals
in the body, especially so when frying foods.

If you are regularly exposed to sunlight, especially to ultra-violet

radiation, or if you are going to be exposed to sunlight for any length of
time, for instance sunbathing, skiing, yachting etc it is best to
supplement your diet with extra antioxidants.

Tobacco smoke
o

Any smoker, and that includes people living with smokers who may
inhale secondary smoke, should look at supplementing their diet with
vitamin C. Although some people would contend that this is excessive,
you should look at supplementing your diet daily with 25 mg of vitamin
C for each cigarette smoked.

Keep in mind that although extra vitamin C would be beneficial, it is

still best to take antioxidants in a combined formula.

X-rays
o

Normal magnetism fields, created in our environment should be

handled by diet, but if exposed to extra X-rays you should consider
supplementing your diet.

Damage

When these excess free radicals have a free reign on our body they cause severe damage to cells,
which can lead to degenerative diseases as well as premature ageing. Free radicals are extremely
active and do not only attack and damage the cell membranes, but will virtually attack all parts of
the cell, including the DNA - the area where the blueprint of the cell is kept and produced.
Therefore, free radicals do not only damage the existing cells, but also attack the DNA, which
leads to faulty translation of genetic material. Antioxidants stop these free radicals in their tracks
and enable the cells to rejuvenate or stabilize for the life process.

Benefits of antioxidants

All antioxidants have a chemical element referred to as a redox potential, which is the
measurement of their ability to be oxidized. They are by this action also classified as reducing
agents which are needed to quickly block the chain reaction caused by free radicals before cell
damage can result.
Considering the fact that the redox equilibrium is important to the bodys coping mechanism, it
follows that antioxidants can influence many health conditions.
In the list that follows we have noted some health conditions that may be positively influenced
when sufficient antioxidants are available in the body.

Acne
o

Ageing skin
o

It can help to boost the immune system and clear the blood.

Aids

To help protect the cell integrity as well as the supportive collagen

tissue.

Alcohol
o

They help in strengthening capillaries as well as helping to prevent

fatty deposits.

Circulatory problems
o

Although antioxidants may not cure cancer, much research has been
done and is still continuing, regarding the role of antioxidants in the
prevention and alleviation of cancer.

Capillary fragility
o

Since free radicals contribute to this problem, the addition of

antioxidants may be helpful.

Cancer
o

Helps to relieve localized oxidative stress and also promote healthy

joint cells.

Bowel inflammation
o

By helping to protect blood vessels from fatty deposits they may help
the veins maintain their elasticity.

Arthritis and joint pain

o

Certain antioxidants help with the control of the histamine release

mechanism, it may be of use for allergies.

Angina, heart and arterial disease

o

Consumption of alcohol causes a host of toxins in the body and

antioxidants are useful in the detoxification process.

Allergies
o

Useful in boosting the immune system, they may be of value to people

with Aids.

It seems to be involved in helping to control fatty deposits in the

arteries, and in maintaining elasticity of the veins and good circulation.

Colds and flu

o

While boosting the immune system they will help to alleviate these
conditions.

Fatigue
o

Gingivitis, gum bleeding and mouth ulcers

o

Although the topical application of vitamin E has long been advocated

to prevent the formation of scar tissue in wound healing, the dietary
supplementation of antioxidants can also be useful in this case.

Stamina
o

As with arthritis, antioxidants are involved in relieving localized

oxidative stress and also promote healthy joint cells.

Scar formation
o

It assists in vein and artery health, it would also be indicated to help

these conditions.

Rheumatism
o

Promotes the growth of tissue and helps prevent DNA destruction, they
are also indicated to assist with memory loss.

Piles and varicose veins

o

Excessive free radicals destroy genetic material and sperm counts may
be lower than normal, which could lead to infertility.

Memory loss
o

Help prevent oxidation processes from hampering recovery.

Male infertility
o

Vitamin C has long been indicated in the treatment of both gingivitis

and mouth ulcers, but a combined antioxidant formula would also be
indicated.

Injuries
o

Useful in releasing oxidized fatty deposits, and in doing so, boosting

energy production.

Antioxidants help to reduce the build-up of peroxide from the body, an

increase in stamina should be experienced when they are abundant in
the body.

Stress

General stress levels, as well as specific female stress during

pregnancy, menopause or when taking oral contraceptives, as well as
stress felt by adolescents while growing up, can benefit from extra
antioxidants.

Wounds
o

The oxidation processes can hamper wound healing and since

antioxidants will help control this, better healing should be promoted
and the immune system boosted in general, which will help to prevent
infections.

Although the list above almost covers the whole spectrum of ills and ailments, it must be noted
that it is not claimed that antioxidants will cure or prevent these conditions, but there is a strong
indication that they may be of assistance.
Different types of antioxidant nutrients

Below is a list of antioxidant nutrients that have been found to be of value. Items marked with an
(*) are included in the Zest for Life Antioxidant formula.

Alpha-Lipoic Acid
o

Bioflavonoids (*)
o

There are thousands of bioflavonoids found in nature, and they are

often referred to as flavonoids.

Rutin
o

It is also called thioctic acid and works in synergy with enzymes in

energy production as well as with the B group vitamins. It is found in
brewers yeast, liver and spinach. Results in a study showed that
alpha-lipoic acid counteracted glycollate-induced free radical toxicity in
rats.

This is a citrus bioflavonoid and has for years been used in conjunction
with vitamin C since they have great synergy together. Results in a
study found that rutin inhibited oxidative damage in pathological
human red blood cells.

Hesperidin
o

This is also a citrus bioflavonoid and is mostly indicated for capillary

health. Results in a study showed that hesperidin taken from orange
peel possessed significant analgesic and anti-inflammatory effects.

Quercetin
o

Procyanidolic oligomers (PCO) (*)

o

Essential Phospholipids (EPL) from Lecithin have become popular as

nutritional supplements because it has been discovered that
populations that consume large amounts of EPLs suffer very low rates
of heart disease, despite the fact that their diets are high in fats and
cholesterol. It is thought that this is due to the ability of the EPLs to
reduce the adhesiveness of platelets in the blood (thus reducing the
bloods tendency to clot), to reduce the blood levels of very low-density
lipoprotein (VLDLs), to reduce the levels of triglycerids in the blood and
to reduce the synthesis of cholesterol in the liver.

Ginkgo Biloba
o

Cysteine is an amino acid, and two molecules of cysteine forms cystine

and this sulfur containing amino acid is most useful in detoxifying the
body. It is also a precursor to glutathione, which protects the liver.

Essential phospholipids (*)

o

Coenzyme Q10, also called Ubiquinone, is produced by the body and is

found in food sources such as nuts and certain oils.

Cysteine
o

Polyphenols are mostly found in green tea, which is an excellent source

of epigallocatechin-gallate, and shows great promise in anti-cancer
research.

Coenzyme Q10 (*)

o

PCOs are present in pine bark, grape seed as well as red wine and
have shown great promise protesting the heart and circulatory system,
preventing histamine release and promoting the health of veins.

Polyphenols (*)
o

Quercetin is found in apple peel and onions and assists the body in
utilizing blood sugar and inhibiting histamine release.

This herb is normally used as a supplement for mental fatigue, a

memory booster, as well as an aphrodisiac, since it assists with
circulation to even the smallest capillaries, and delivers oxygen and
glucose to the nerves.

Glutathione

Grape Seed Extract (*)

o

Selenium is a component of the enzyme glutathione peroxidase found

in nearly every cell of the body. This trace element is present in soil
and is abundant in Brazil nuts, seafood, poultry and meats.

Superoxide Dismutase
o

Pine Bark, also known as pycnogenol, was discovered and the

extraction patented in 1950. It has the same active ingredient as grape
seed extract.

Selenium (*)
o

The hormone melatonin is a powerful antioxidant, and is produced by

the pineal gland and is also indicated in our sleep patterns and has
also been found to have a beneficial effect on the aging process.

Pine Bark (*)

o

Unlike normal tea, green tea is not fermented which is why it contains
polyphenols. The EGCG (epigallocatechin-gallate) contained in green
tea is especially indicated to be useful in the treatment of cancers.

Melatonin
o

Grape seed contains procyanidolic oligomers, which are also referred

to as pycnogenols, and have the same active ingredient as that of pine
bark. It is both water and oil soluble, which makes it attractive as an
antioxidant, since it can have both an influence on the cell membrane
and cell interior.

Green Tea (*)

o

This is classed as a tripeptide, is produced by the liver and not only

does it work in detoxifying the liver, but also helps to maintain the
integrity of red blood cells and to protect white blood cells.

This is an enzyme, which helps to revitalize cells, and also assists in

reducing cell destruction and is specifically beneficial in protecting the
mitochondria of the cell where the cells genetic information is stored.

Vitamin A and Beta-Carotene (*)

o

This fat-soluble vitamin is also required for bone formation,

gastrointestinal and eye health and in assisting the immune system
and skin. Results of a double blind, placebo controlled study found that
supplementation with beta-carotene for two weeks moderately

enhanced certain aspects of immune response in healthy male

cigarette smokers.

Vitamin C (*)
o

Vitamin E (*)
o

Many nutritionists like Adelle Davis promoted the use of vitamin C, and
the medical fraternity now accepts the fact that there are countless
uses for this vitamin. It is required for the manufacture of collagen in
the body, and helps boost the effectiveness of other antioxidants in the
body.

This vitamin is especially helpful in preventing the oxidation of lipids,

assists in the utility of oxygen and selenium. A review article notes the
many positive aspects of vitamin E with respect to the aging process,
including its ability to modify free radicals, deficiency of protein
synthesis, ameliorate the functionality of important body organs, help
maintain bone matrix trophysm.

Zinc (*)
o

Zinc on its own has antioxidant properties, yet also forms part of
superoxide dismutase while it helps with vitamin A absorption and
promotes glandular health.

FREE RADICAL FORMATION

Atoms are most stable in the ground state. An atom is considered to be "ground"
when every electron in the outermost shell has a complimentary electron that spins
in the opposite direction. By definition a free radical is any atom (e.g. oxygen,
nitrogen) with at least one unpaired electron in the outermost shell, and is capable
of independent existence (13). A free radical is easily formed when a covalent bond
between entities is broken and one electron remains with each newly formed atom
(13). Free radicals are highly reactive due to the presence of unpaired electron(s).
The following literature review addresses only radicals with an oxygen center. Any
free radical involving oxygen can be referred to as reactive oxygen species (ROS).
Oxygen centered free radicals contain two unpaired electrons in the outer shell.
When free radicals steal an electron from a surrounding compound or molecule a
new free radical is formed in its place. In turn the newly formed radical then looks to
return to its ground state by stealing electrons with antiparallel spins from cellular
structures or molecules. Thus the chain reaction continues and can be "thousand of
events long." (7). The electron transport chain (ETC), which is found in the inner
mitochondrial membrane, utilizes oxygen to generate energy in the form of
adenosine triphosphate (ATP). Oxygen acts as the terminal electron acceptor within
the ETC. The literature suggests that anywhere from 2 to 5% (14) of the total
oxygen intake during both rest and exercise have the ability to form the highly
damaging superoxide radical via electron escape. During exercise oxygen
consumption increases 10 to 20 fold to 35-70 ml/kg/min. In turn, electron escape
from the ETC is further enhanced. Thus, when calculated, .6 to 3.5 ml/kg/min of the
total oxygen intake during exercise has the ability to form free radicals (4). Electrons
appear to escape from the ETS at the ubiqunone-cytochrome c level (14).
PEROXIDATION
Polyunsaturated fatty acids (PUFAs) are abundant in cellular membranes and in lowdensity lipoproteins (LDL) (4). The PUFAs allow for fluidity of cellular membranes. A
free radical prefers to steal electrons from the lipid membrane of a cell, initiating a
free radical attack on the cell known as lipid peroxidation. Reactive oxygen species
target the carbon-carbon double bond of polyunsaturated fatty acids. The double
bond on the carbon weakens the carbon-hydrogen bond allowing for easy
dissociation of the hydrogen by a free radical. A free radical will steal the single
electron from the hydrogen associated with the carbon at the double bond. In turn
this leaves the carbon with an unpaired electron and hence becomes a free radical.
In an effort to stabilize the carbon-centered free radical molecular rearrangement
occurs. The newly arranged molecule is called a conjugated diene (CD). The CD
then very easily reacts with oxygen to form a proxy radical. The proxy radical steals

an electron from another lipid molecule in a process called propagation. This

process then continues in a chain reaction (9)
TYPES OF FREE RADICALS
There are numerous types of free radicals that can be formed within the body. This
web site is only concerned with the oxygen centered free radicals or ROS. The most
common ROS include: the superoxide anion (O2-), the hydroxyl radical (OH ),
singlet oxygen (1O2 ), and hydrogen peroxide (H2O2) Superoxide anions are formed
when oxygen (O2) acquires an additional electron, leaving the molecule with only
one unpaired electron. Within the mitochondria O2- is continuously being formed.
The rate of formation depends on the amount of oxygen flowing through the
mitochondria at any given time. Hydroxyl radicals are short-lived, but the most
damaging radicals within the body. This type of free radical can be formed from O2and H2O2 via the Harber-Weiss reaction. The interaction of copper or iron and H2O2
also produce OH as first observed by Fenton. These reactions are significant as the
substrates are found within the body and could easily interact (9). Hydrogen
peroxide is produced in vivo by many reactions. Hydrogen peroxide is unique in that
it can be converted to the highly damaging hydroxyl radical or be catalyzed and
excreted harmlessly as water. Glutathione peroxidase is essential for the conversion
of glutathione to oxidized glutathione, during which H2O2 is converted to water (2).
If H2O2 is not converted into water 1O2 is formed. Singlet oxygen is not a free
radical, but can be formed during radical reactions and also cause further reactions.
Singlet oxygen violates Hund's rule of electron filling in that it has eight outer
electrons existing in pairs leaving one orbital of the same energy level empty. When
oxygen is energetically excited one of the electrons can jump to empty orbital
creating unpaired electrons (13). Singlet oxygen can then transfer the energy to a
new molecule and act as a catalyst for free radical formation. The molecule can also
interact with other molecules leading to the formation of a new free radical.
CATALYSTS
All transition metals, with the exception of copper contain one electron in their
outermost shell and can be considered free radicals. Copper has a full outer shell,
but loses and gains electrons very easily making itself a free radical (9). In addition
iron has the ability to gain and lose electrons (i.e. (Fe2+Fe3+) very easily. This
property makes iron and copper two common catalysts of oxidation reactions. Iron is
major component of red blood cells (RBC). A possible hypothesis is that the stress
encountered during may break down RBC releasing free iron. The release of iron can
be detrimental to cellular membranes because of the pro-oxidation effects it can
have. Zinc only exists in one valence (Zn2+) and does not catalyze free radical
formation. Zinc may actually act to stop radical formation by displacing those
metals that do have more than one valence.

MEASUREMENT OF FREE RADICALS

Free radicals have a very short half-life, which makes them very hard to measure in
the laboratory. Multiple methods of measurement are available today, each with
their own benefits and limits. Radicals can be measured using electron spin
resonance and spin trapping methods. The methods are both very sophisticated and
can trap even the shortest­lived free radical. Exogenous compounds with a
high affinity for free radicals (i.e. xenobiotics) are utilized in the spin techniques.
The compound and radical together form a stable entity that can be easily
measured. This indirect approach has been termed "fingerprinting." (12). However,
this method is not 100% accurate. Spin-trapping collection techniques have poor
sensitivity, which can skew results (1) A commonly used alternate approach
measures markers of free radicals rather than the actual radical. These markers of
oxidative stress are measured using a variety of different assays. These assays are
described below. When a fatty acid is peroxidized it is broken down into aldehydes,
which are excreted. Aldehydes such as thiobarbituric acid reacting substances
(TBARS) have been widely accepted as a general marker of free radical production
(3). The most commonly measured TBARS is malondialdehyde (MDA) (13). The TBA
test has been challenged because of its lack of specificity, sensitivity, and
reproducibility. The use of liquid chromatography instead spectrophotometer
techniques help reduce these errors (15). In addition, the test seems to work best
when applied to membrane systems such as microsomes (8). Gases such as
pentane and ethane are also created as lipid peroxidation occurs. These gases are
expired and commonly measured during free radical research (13). Dillard et al. (6)
was one of the first to determine that expired pentane increased as VO2 max
increased. Kanter et al. (11) has reported that serum MDA levels correlated closely
with blood levels of creatine kinase, an indicator of muscle damage. Lastly,
conjugated dienes (CD) are often measured as indicators of free radical production.
Oxidation of unsaturated fatty acids results in the formation of CD. The CD formed
are measured and provide a marker of the early stages of lipid peroxidation (9). A
newly developed technique for measuring free radical production shows promise in
producing more valid results. The technique uses monoclonal antibodies and may
prove to be the most accurate measurement of free radicals. However, until further
more reliable techniques are established it is generally accepted that two or more
assays be utilized whenever possible to enhance validity (9).
PHYSIOLOGICAL EFFECTS
Under normal conditions (at rest) the antioxidant defense system within the body
can easily handle free radicals that are produced. During times of increased oxygen
flux (i.e. exercise) free radical production may exceed that of removal ultimately
resulting in lipid peroxidation. Free radicals have been implicated as playing a role in
the etiology of cardiovascular disease, cancer, Alzheimer's disease, and Parkinson's
disease. While worthy of a discussion these conditions are not the focus of the

current literature review. This literature review will only examine the current
literature addressing the relationship between free radicals and exercise, which is
introduced below. The driving force behind these topics is lipid peroxidation. By
preventing or controlling lipid peroxidation the concomitant effects discussed below
would be better controlled.
REQUIREMENT
Oxygen consumption greatly increases during exercise, which leads to increased
free radical production. The body counters the increase in free radical production
through the antioxidant defense system. When free radical production exceeds
clearance oxidative damage occurs. Free radicals formed during chronic exercise
may exceed the protective capacity of the antioxidant defense system, thereby
making the body more immune to disease and injury. Therefore the need for
antioxidant supplementation is discussed.
FATIGUE
A free radical attack on a membrane usually damages a cell to the point that it must
be removed by the immune system. If free radical formation and attack are not
controlled within the muscle during exercise a large quantity of muscle could easily
be damaged. Damaged muscle could in turn inhibit performance by the induction of
fatigue. The role individual antioxidants have in inhibiting this damage has been
addressed within the review of the four antioxidants that follows.
RECOVERY
One of the first steps in recovery from exercise induced muscle damage is an acute
inflammatory response at the site of muscle damage. Free radicals are commonly
associated with the inflammatory response and are hypothesized to be greatest
twenty-four hours after completion of a strenuous exercise session. If this theory
were valid then antioxidants would play a major role in helping prevent this
damage. However, if antioxidant defense systems are inadequate or not elevated
during the post-exercise infiltration period free radicals could further damage
muscle beyond that acquired during exercise. This in turn would increase the time
needed to recover from an exercise bout.
IMPORTANCE OF FREE RADICALS
This section has focused only on the negatives associated with free radical
production. However, free radicals are naturally produced by some systems within
the body and have beneficial effects that cannot be overlooked. The immune
system is the main body system that utilizes free radicals. Foreign invaders or
damaged tissue is marked with free radicals by the immune system. This allows for

determination of which tissue need to be removed from the body. Because of this
some question the need for antioxidant supplementation, as they believe
supplementation can actually decrease the effectiveness of the immune system.
ANTIOXIDANT DEFENSES
Antioxidant means "against oxidation." Antioxidants work to protect lipids from
peroxidation by radicals. Antioxidants are effective because they are willing to give
up their own electrons to free radicals. When a free radical gains the electron from
an antioxidant it no longer needs to attack the cell and the chain reaction of
oxidation is broken (4). After donating an electron an antioxidant becomes a free
radical by definition. Antioxidants in this state are not harmful because they have
the ability to accommodate the change in electrons without becoming reactive. The
human body has an elaborate antioxidant defense system. Antioxidants are
manufactured within the body and can also be extracted from the food humans eat
such as fruits, vegetables, seeds, nuts, meats, and oil. There are two lines of
antioxidant defense within the cell. The first line, found in the fat-soluble cellular
membrane consists of vitamin E, beta-carotene, and coenzyme Q (10). Of these,
vitamin E is considered the most potent chain breaking antioxidant within the
membrane of the cell. Inside the cell water soluble antioxidant scavengers are
present. These include vitamin C, glutathione peroxidase, superoxide dismutase
(SD), and catalase (4). Only those antioxidants that are commonly supplemented
(vitamins A, C, E and the mineral selenium) are addressed in the literature review
that follows.