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What are free radicals? Why are they damaging to the human body?

And how
does vitamin E and the other antioxidant nutrients help protect the body against
free radical damage? We?ll attempt to answer these questions and help you
understand why eating 5-8 servings per day of anti-oxidant rich fruits and
vegetables can benefit your health. But first, a little background?

Background: A Brief Look at Chemical Bonding

To understand the way that free radicals and antioxidants interact, you must first
understand a bit about cells and molecules. So here's a (very) brief refresher
course in Physiology/Chemistry 101: The human body is composed of many
different types of cells. Cells are composed of many different types of molecules.
Molecules consist of one or more atoms of one or more elements joined by chemical bonds.

As you probably remember from your old high school days, atoms consist of a nucleus, neutrons, protons and
electrons. The number of protons (positively charged particles) in the atom?s nucleus determines the number of
electrons (negatively charged particles) surrounding the atom. Electrons are involved in chemical reactions and are
the substance that bonds atoms together to form molecules. Electrons surround, or "orbit" an atom in one or more
shells. The innermost shell is full when it has two electrons. When the first shell is full, electrons begin to fill the
second shell. When the second shell has eight electrons, it is full, and so on.

The most important structural feature of an atom for determining its chemical behavior is the number of electrons in
its outer shell. A substance that has a full outer shell tends not to enter in chemical reactions (an inert substance).
Because atoms seek to reach a state of maximum stability, an atom will try to fill it?s outer shell by:

• Gaining or losing electrons to either fill or empty its outer shell


• Sharing its electrons by bonding together with other atoms in order to complete its outer shell

Atoms often complete their outer shells by sharing electrons with other atoms. By sharing electrons, the atoms are
bound together and satisfy the conditions of maximum stability for the molecule.

How Free Radicals are Formed

Normally, bonds don?t split in a way that leaves a molecule with an odd, unpaired electron. But when weak bonds
split, free radicals are formed. Free radicals are very unstable and react quickly with other compounds, trying to
capture the needed electron to gain stability. Generally, free radicals attack the nearest stable molecule, "stealing" its
electron. When the "attacked" molecule loses its electron, it becomes a free radical itself, beginning a chain reaction.
Once the process is started, it can cascade, finally resulting in the disruption of a living cell.

Some free radicals arise normally during metabolism. Sometimes the body?s immune system?s cells purposefully
create them to neutralize viruses and bacteria. However, environmental factors such as pollution, radiation, cigarette
smoke and herbicides can also spawn free radicals.

Normally, the body can handle free radicals, but if antioxidants are unavailable, or if the free-radical production
becomes excessive, damage can occur. Of particular importance is that free radical damage accumulates with age.
How Antioxidants May Prevent Against Free Radical Damage

The vitamins C and E, are thought to protect the body against the destructive effects of free radicals. Antioxidants
neutralize free radicals by donating one of their own electrons, ending the electron-"stealing" reaction. The
antioxidant nutrients themselves don?t become free radicals by donating an electron because they are stable in
either form They act as scavengers, helping to prevent cell and tissue damage that could lead to cellular damage
and disease.

Vitamin E ? The most abundant fat-soluble antioxidant in the body. One of the most efficient chain-breaking
antioxidants available. Primary defender against oxidation. Primary defender against lipid peroxidation (creation of
unstable molecules containing more oxygen than is usual).

Vitamin C ? The most abundant water-soluble antioxidant in the body. Acts primarily in cellular fluid. Of particular
note in combating free-radical formation caused by pollution and cigarette smoke. Also helps return vitamin E to its
active form.

The Antioxidants and Disease Prevention

• Heart Disease ? Vitamin E may protect against cardiovascular disease by defending against LDL oxidation
and artery-clogging plaque formation.
• Cancer ? Many studies have correlated high vitamin C intakes with low rates of cancer, particularly cancers
of the mouth, larynx and esophagus.

The Lesson: Eat Your Fruits and Vegetables!

The antioxidants are believed to help protect the body from free-radical damage. But before you go out and stock
your pantry with mega-doses of these vitamins, be warned: more is not always better. The long-term effect of large
doses of these nutrients has not been proven. Other chemicals and substances found in natural sources of
antioxidants may also be responsible for the beneficial effects. So for now, the best way to ensure adequate intake of
the antioxidant nutrients is through a balanced diet consisting of 5-8 servings of fruits and vegetables per day.

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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


low-density 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 peroxy radical. The
peroxy 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 O2- and 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.

REFERENCES
1. Acworth, I.N., and B. Bailey. Reactive Oxygen Species. In: The handbook of
oxidative metabolism. Massachusetts: ESA Inc., 1997, p. 1-1 to 4-4.
2. Alessio, H.M., and E.R. Blasi. Physical activity as a natural antioxidant booster and
its effect on a healthy lifestyle. Res. Q. Exerc. Sport. 68 (4): 292-302, 1997.
[Abstract]
3. Clarkson P. M. Antioxidants and physical performance. Crit.Rev. Food Sci. Nutr.
35: 131-141, 1995. [Abstract]
4. Dekkers, J. C., L. J. P. van Doornen, and Han C. G. Kemper. The Role of
Antioxidant Vitamins and Enzymes in the Prevention of Exercise-Induced Muscle
Damage. Sports Med 21: 213-238, 1996. [Abstract]
5. Del Mastero, R.F. An approach to free radicals in medicine an biology. Acta.
Phyiol. Scand. 492: 153-168, 1980.
6. Dillard, C.J., R.E. Litov, W.M. Savin, E.E. Dumelin, and A.L. Tappel. Effects of
exercise, vitamin E, and ozone on pulmonary function and lipid peroxidation. J.
Appl. Physiol. 45: 927, 1978. [Abstract]
7. Goldfarb, A. H. Nutritional antioxidants as therapeutic and preventive modalities in
exercise-induced muscle damage. Can. J. Appl. Physiol. 24: 249-266, 1999.
[Abstract]
8. Halliwell, B., and S. Chirico. Lipid peroxidation: Its mechanism, measurement, and
signficance. Am. J. Clin. Nutr. 57: 715S-725S, 1993. [Abstract]
9. Halliwell, B., and J.M.C. Gutteridge. The chemistry of oxygen radicals and other
oxygen-derived species. In: Free Radicals in Biology and Medicine. New York:
Oxford University Press, 1985, p. 20-64.

10. Kaczmarski, M., J. Wojicicki, L. Samochowiee, T. Dutkiewicz, and Z. Sych. The


influence of exogenous antioxidants and physical exercise on some parameters
associated with production and removal of free radicals. Pharmazie 54: 303-306,
1999. [Abstract]

Antioxidants and Free radicals

Antioxidants are intimately involved in the prevention of cellular damage -- the common
pathway for cancer, aging, and a variety of diseases. The scientific community has begun
to unveil some of the mysteries surrounding this topic, and the media has begun whetting
our thirst for knowledge. Athletes have a keen interest because of health concerns and the
prospect of enhanced performance and/or recovery from exercise. The purpose of this
article is to serve as a beginners guide to what antioxidants are and to briefly review their
role in exercise and general health. What follows is only the tip of the iceberg in this
dynamic and interesting subject.

It's the radicals, man

Free radicals are atoms or groups of atoms with an odd (unpaired) number of electrons
and can be formed when oxygen interacts with certain molecules. Once formed these
highly reactive radicals can start a chain reaction, like dominoes. Their chief danger
comes from the damage they can do when they react with important cellular components
such as DNA, or the cell membrane. Cells may function poorly or die if this occurs. To
prevent free radical damage the body has a defense system of antioxidants.

Antioxidants are molecules which can safely interact with free radicals and terminate the
chain reaction before vital molecules are damaged. Although there are several enzyme
systems within the body that scavenge free radicals, the principle micronutrient (vitamin)
antioxidants are vitamin E, beta-carotene, and vitamin C. Additionally, selenium, a trace
metal that is required for proper function of one of the body's antioxidant enzyme
systems, is sometimes included in this category. The body cannot manufacture these
micronutrients so they must be supplied in the diet.

Vitamin E : d-alpha tocopherol. A fat soluble vitamin present in nuts, seeds, vegetable
and fish oils, whole grains (esp. wheat germ), fortified cereals, and apricots. Current
recommended daily allowance (RDA) is 15 IU per day for men and 12 IU per day for
women.

Vitamin C : Ascorbic acid is a water soluble vitamin present in citrus fruits and juices,
green peppers, cabbage, spinach, broccoli, kale, cantaloupe, kiwi, and strawberries. The
RDA is 60 mg per day. Intake above 2000 mg may be associated with adverse side
effects in some individuals.

Beta-carotene is a precursor to vitamin A (retinol) and is present in liver, egg yolk, milk,
butter, spinach, carrots, squash, broccoli, yams, tomato, cantaloupe, peaches, and grains.
Because beta-carotene is converted to vitamin A by the body there is no set requirement.
Instead the RDA is expressed as retinol equivalents (RE), to clarify the relationship.
(NOTE: Vitamin A has no antioxidant properties and can be quite toxic when taken in
excess.)

Preventing cancer and heart disease -- do antioxidants help?

Epidemiologic observations show lower cancer rates in people whose diets are rich in
fruits and vegetables. This has lead to the theory that these diets contain substances,
possibly antioxidants, which protect against the development of cancer. There is currently
intense scientific investigation into this topic. Thus far, none of the large, well designed
studies have shown that dietary supplementation with extra antioxidants reduces the risk
of developing cancer. In fact one study demonstrated an increased risk of lung cancer in
male smokers who took antioxidants vs. male smoker who did not supplement. Whether
this effect was from the antioxidants is unknown but it does raise the issue that
antioxidants may be harmful under certain conditions.

Antioxidants are also thought to have a role in slowing the aging process and preventing
heart disease and strokes, but the data is still inconclusive. Therefore from a public health
perspective it is premature to make recommendations regarding antioxidant supplements
and disease prevention. New data from ongoing studies will be available in the next few
years and will shed more light on this constantly evolving area. Perhaps the best advice,
which comes from several authorities in cancer prevention, is to eat 5 servings of fruit or
vegetables per day.

Exercise and oxidative damage

Endurance exercise can increase oxygen utilization from 10 to 20 times over the resting
state. This greatly increases the generation of free radicals, prompting concern about
enhanced damage to muscles and other tissues. The question that arises is, how
effectively can athletes defend against the increased free radicals resulting from exercise?
Do athletes need to take extra antioxidants?

Because it is not possible to directly measure free radicals in the body, scientists have
approached this question by measuring the by-products that result from free radical
reactions. If the generation of free radicals exceeds the antioxidant defenses then one
would expect to see more of these by-products. These measurements have been
performed in athletes under a variety of conditions.

Several interesting concepts have emerged from these types of experimental studies.
Regular physical exercise enhances the antioxidant defense system and protects against
exercise induced free radical damage. This is an important finding because it shows how
smart the body is about adapting to the demands of exercise. These changes occur slowly
over time and appear to parallel other adaptations to exercise.

On the other hand, intense exercise in untrained individuals overwhelms defenses


resulting in increased free radical damage. Thus, the "weekend warrior" who is
predominantly sedentary during the week but engages in vigorous bouts of exercise
during the weekend may be doing more harm than good. To this end there are many
factors which may determine whether exercise induced free radical damage occurs,
including degree of conditioning of the athlete, intensity of exercise, and diet.

Can antioxidant supplements prevent exercise induced damage or


enhance recovery from exercise?

Although it is well known that vitamin deficiencies can create difficulties in training and
recovery, the role of antioxidant supplementation in a well nourished athlete is
controversial. The experimental studies are often conflicting and conclusions are difficult
to reach. Nevertheless, most of the data suggest that increased intake of vitamin E is
protective against exercise induced oxidative damage. It is hypothesized that vitamin E is
also involved in the recovery process following exercise. Currently, the amount of
vitamin E needed to produce these effects is unknown. The diet may supply enough
vitamin E in most athletes, but some may require supplementation. There is no firm data
to support the use of increased amounts of the other antioxidants.

Performance

In general, antioxidant supplements have not been shown to be useful as performance


enhancers. The one exception to this is vitamin E which has been shown to be useful in
athletes exercising at high altitudes. A placebo controlled study done on mountaineers
demonstrated less free radical damage and decline in anaerobic threshold in those athletes
supplemented with vitamin E. Although difficult to generalize, this finding suggests that
supplementation with vitamin E might be beneficial in those triathletes who are adapting
to higher elevations.

How much is enough?


Although there is little doubt that antioxidants are a necessary component for good
health, no one knows if supplements should be taken and, if so, how much. Antioxidants
supplements were once thought to be harmless but increasingly we are becoming aware
of interactions and potential toxicity. It is interesting to note that, in the normal
concentrations found in the body, vitamin C and beta-carotene are antioxidants; but at
higher concentrations they are pro-oxidants and, thus, harmful. Also, very little is known
about the long term consequences of megadoses of antioxidants. The body's finely tuned
mechanisms are carefully balanced to withstand a variety of insults. Taking chemicals
without a complete understanding of all of their effects may disrupt this balance.

Recommendations

• Follow a balanced training program that emphasizes regular exercise and eat 5
servings of fruit or vegetables per day. This will ensure that you are developing
your inherent antioxidant systems and that your diet is providing the necessary
components.
• Weekend warriors should strongly consider a more balanced approach to exercise.
Failing that, consider supplementation.
• For extremely demanding races (such as an ultradistance event), or when adapting
to high altitude, consider taking a vitamin E supplement (100 to 200 IU,
approximately 10 times the RDA) per day for several weeks up to and following
the race.
• Look for upcoming FDA recommendations, but be wary of advertising and media
hype.
• Do not oversupplement.

Selected References

1. The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and
Other Cancers in Male Smokers New England Journal of Medicine (NEJM). vol
330 (15) Apr. 14, 1994. pp 1029-1035.
2. A Clinical Trial of Antioxidant Vitamins to Prevent Colorectal Adenoma NEJM,
vol 331 (3). July 21, 1994. pp 141-147
3. Antioxidant Vitamins -- Benefits Not Yet Proved (editorial) NEJM vol 330 (15)
Apr. 14, 1994. p 1080 - 1081
4. Antioxidants and Physical Performance (review) Critical Reviews in Food
Science and Nutrition, 35(1&2):131-141 (1995).
5. Increased blood antioxidant systems of runners in response to training load.
Clinical Science (1991). 80, 611-618.
6. Exercise, Oxidative Damage and Effects of Antioxidant Manipulation (review).
Journal of Nutrition 122(3 suppl): 766-73, 1992 Mar.
7. Antioxidants: role of supplementation to prevent exercise-induced oxidative stress
(review). Medicine and Science in Sports and Exercise. 25(2):232-6, 1993 Feb.
8. Prospects for the use of antioxidant therapies.(Review). Drugs 49(3):345-61,
1995 Mar.