one is talking about antioxidants ! A major pharmaceutical
company runs full-page ads in newsmagazines pointing
out the dangers of oxidative stress while mentioning
that three of their multivitamins products can protect
you from excess oxidation. Sales of vitamins have
been increasing by 20 to 30 percent per year, and
much of the growth can be credited to antioxidant
formulas. Animal studies and several large controlled
human trials point to the wisdom of taking antioxidant
supplements, especially vitamin E to help prevent
heart disease and cancer.
It is useful to know what oxidative stress is and
which compounds normally found in our bodies protect
us from the damaging effects of oxygen. This demonstrate
how antioxidants can be protective, and it can also
help you decide what might be the most important antioxidant
for you to take.
This chapter explains antioxidant in the context of
a regimen for good health.
some microorganisms (and plants), known as anaerobes,
can live without oxygen; most, including humans, need
oxygen. Anaerobes make energy by breaking down preformed
carbohydrates and proteins, but energy-wise this process
is inefficient. Most microorganisms and all animals
(including humans) use oxygen to "burn"
or oxidize foods into carbon dioxide and water. A
great deal of energy is produced as a result of this
process. Metabolizing one molecule of glucose with
oxygen produces about four times as much energy as
could produced if the same molecule were to be metabolized
without oxygen. In our bodies, carbon from food is
oxidized to carbon dioxide. Oxygen superoxide grabs
electrons from a neighboring source and combines with
hydrogen to form water. The reduction of oxygen is
accomplished in special structures inside body cells
called mitochondria. Carbon dioxide that results from
this process is eliminated in our breath, urine, and
sweat. Plants use the carbon dioxide we produce to
make oxygen. This is a very nice ecosystem, and one
we need to be careful not to disrupt.
But the system isn't perfect. Did you ever notice
how rubber or plastic becomes brittle and cracks after
some time has passed? This happens when these materials
react with oxygen in the air to produce a modified
plastic or rubber that is not as soft and flexible
as the original. We live in an environment filled
with oxygen, and this is exactly what happens to our
bodies as we age. Our skin loses flexibility and starts
to wrinkle; our organs don't work as well; our blood
vessels get clogged with plaque, putting us at risk
at a heart attack or stroke; and we are at a higher
risk for cancer. Oxygen is not the only reason that
our bodies deteriorate, but it is part of the picture.
Oxygen damage body tissues after long periods of exposure
because tiny amounts of chemically reactive oxygen
are produced in the everyday reduction of oxygen in
the mitochondria. This reaction sometimes occur in
other parts of our bodies as well. Reactive oxygen
molecules that cause the problems described above
are called free radicals. They will reach out to whatever
is close by and attach to it. Let's say, for example,
that the free radical combines with a lipid molecule
in a kidney cell membrane. The lipid molecule is now
a reactive radical itself and can react with another
oxygen molecule to form a lipid peroxide radical.
Meanwhile, a neighboring radical reacts with oxygen
in the same process. This can continue until the kidney
cell is permanently damaged. In theory, a single radical
could destroy us with this chain reaction!
Actually, there are many different kinds of oxygen
radicals. The most important are superoxides, hydroxy
radicals, and perhydroxy radicals. These are extremely
reactive and will combine immediately with anything
nearby. There is another reactive from of oxygen as
well, called singlet oxygen.
Oxidative injury is implicated in a long list of disease.
Following are some of the more important examples.
RELATED TO OXYGEN RADICALS
of the Arteries (Atherosclerosis)
have "good cholesterol" and "bad cholesterol"
in our bodies. Good cholesterol is attached to lipids
called HDL (high-density lipoproteins). Bad cholesterol
is attached to LDL (low-density lipoproteins). One
reason that the LDL cholesterol is bad is that it
can from plaques in our arteries. When a plaque cracks
or is otherwise activated, a blood clot can from that
blocks blood flow through the artery. If the clot
is in an artery that supplies heart muscle, the blood
supply to part of the heart is blocked. This lead
to chest pain or a heart attack. If the clogged arteries
carries blood to the brain, a stroke or TIA can develop.
If the clogged artery is in the leg, pain develops
on exercise, and in very severe cases leg amputation
may be needed.
In the past decade it has become apparent that the
free 0 radical oxidation of LDL is important to the
process of plaque formation. This is one of the most
important findings for heart disease and stroke prevention
to date and provides many ways for people to help
decrease their risk of heart disease.
Unmodified LDL does not begin the process of plaque
formation. It can be inappropriately oxidized in the
artery wall, though. Once LDL reacts with an oxygen
radical, it is seen as a foreign substance by body
defense systems and is attacked by protective cells
called macrophages. Unfortunately, the process can
be destructive, and the oxidized LDL sets up an inflammation
in the outer layer of the artery that leads to a "fatty
streak" and, later, a plaque deposit. Both can
start the process of blood clotting. Chemicals, including
antioxidant vitamins, that neutralize free radicals
can help block plaque formation and may reduce the
risk of heart attack and stroke.
Complications of Diabetes
glucose levels in blood and tissues that result from
diabetes lead to increased LDL oxidation. Diabetes
have an increased incidence of coronary and vascular
diseases, and antioxidants have the potential of decreasing
some of the LDL oxidation associated with diabetes.
DNA in our cell nuclei to free radicals may result
in DNA strand breaks and mutations, leading to cancer.
Chronic inflammation and injury generate free radicals
as part of the process, which helps explain why these
conditions increase the risk for the development of
cancers. For example, the hepatitis viruses often
cause a chronic liver infection that sharply increases
the risk of liver cancer. The inflammation caused
by inhaled asbestos results in high risk of lung cancer.
Antioxidants have the potential to decrease cancer
risks by neutralizing the free radicals causing damage.
cells whose job is to engulf and destroy bacteria
and damaged tissue particles accomplish this by producing
short bursts of hydrogen peroxide and superoxide.
For reasons that are not well understood, the process
can get out of hand and these chemicals set off reactions
like the one outlined earlier, leading to tissue injury.
The reaction products of free radicals are detected
in synovial fluid. The chain reaction sequence described
earlier is probably important is spreading the inflammation
and damage. Arthritis is one example of this situation,
and antioxidants have the potential to help prevent
blood flow to an organ or tissue is temporarily shut
off and then restarted, the influx of oxygenated blood
causes injury over and above that caused by the temporary
oxygen loss. Apparently, a lack of oxygen reduces
the ability of body tissues to neutralize radicals.
When radicals are generated with the influx of oxygen,
damage results. This is a problem in organ transplantation
and heart surgery, where blood supply is temporarily
interrupted during the procedure. Antioxidants have
the potential to reduce this injury.
reactions certainly play a role in declining body
function as we age. The immune system weakens, blood
vessels get stiff and clogged, and organ function
begins to decline. DNA strand breaks result in mutations
that may start cancers. Cigarette smoke, ionizing
radiation, and certain chemicals all increase the
amount of free radicals and accelerate the aging process.
For example, the wrinkled facial skin of the longtime
smoker is due to free radical damage to the fabric
to the skin by way of reactions discussed here. Antioxidants
have the potential to minimize some aspects of the
infants who receive life-saving oxygen sometimes suffer
damage to the retina of their eyes because the protective
systems that neutralize oxygen free radicals are not
yet in place. Degeneration of the retina, common in
the elderly, is thought to be due in part to the inability
of eye tissue to neutralize free radicals. Antioxidants
have the potential to help prevent certain eye diseases.
could cite many other examples of conditions where
oxygen radicals are thought to play an important role.
If oxygen radical reactions could be blocked or minimized
by drug or vitamin treatment, we might not cure disease,
but we would certainly have a valuable treatment and
BODY'S DEFENSES AGAINST FREE RADICALS
radical reactions went unchecked, we would all have
a very short lifespan. Fortunately, we are well equipped
to survive in an oxygen - rich atmosphere. The burning
questions are : Can we further enhance these protective
mechanisms with dietary supplements? If we accomplish
this, will it result in better health? We believe
the answer to both questions is a resounding yes.
First let us consider our natural protective mechanisms
and then see how several vitamins fit in. The most
direct way to block free-radical-induced damage is
to neutralize the radical where it is generated. A
critically important nutrient, vitamin E, is well
poised to do this. The chemistry of vitamin E is nearly
perfect for its task. It dissolves in fat, so it can
move in and through the lipidlike cell membranes.
It can pick up that lone unpaired electron from a
carbon-centered or oxygen radical to form a less reactive
vitamin E radical.
Vitamin E is considered a chain-breaking free-radical
scavenger because it removes the radical and stabilizes
it. The vitamin E radical is chemically much more
stable than other radicals. As such, it doesn't do
damage to neighboring molecules. Eventually, however,
we need to regenerate the E and to neutralize the
vitamin E radical. This is done with the help of another
remarkable vitamin, vitamin C. Unlike vitamin E, vitamin
C dissolves in water and can accept the unpaired electron
from E sitting in the lipid membrane. Now the radical
is the vitamin C in the fluid outside the cell membrane.
The vitamin C by enzymes with the aid of NADH, a coenzyme
form of niacin. Now we are out of danger thanks to
More protective modalities exist as well. An enzyme
called superoxide dismutase is also very important.
This enzyme causes the inactivation of superoxide
to form less reactive hydrogen peroxide and oxygen.
There are two superoxide dismutase enzymes. One is
in cell mitochondria and contains manganese. The other
is found in fluid outside the cell and contains copper
Hydrogen peroxide, generated by the breakdown of superoxide,
requires either of two other enzymes, glutathione
peroxidase or catalase, to convert the reactive hydrogen
peroxide molecule to water and oxygen. You may have
seen catalase in action if you have ever put hydrogen
peroxide liquid on an a open wound. The "fizz"
is the oxygen released by the action of catalase in
the wound on the added hydrogen peroxide.
Earlier we mentioned singlet oxygen as another reactive
molecule. The carotenoids, precursors of vitamin A,
are chemically designed to neutralize singlet oxygen.
Beta carotene is the most well known carotenoid, but
there are many others. Other chemicals in the body
can also react with radicals to render them harmless.
These includes melatonin, coenzyme Q10, bioflavonoids,
lycopene, and uric acid, but their exact roles are
less well established.
scavenger and antioxidant
for functioning of
glutathione peroxidase, needed
to stop polymerization
for regeneration of glutathione
for regeneration of glutathione
for regeneration of glutathione
for regeneration of superoxide dismutase
Strong fat-soluble and water-soluble
there are yet more protective mechanisms. Earlier
we said that lipid peroxides are dangerous because
they undergo complex reactions that can damage a cell
or membrane. Several vitamins and one mineral are
involved in stopping this dangerous reaction. An enzyme
called glutathione peroxidase stimulates the conversion
of organic peroxides to relatively harmless organic
alcohols. This critical enzyme requires selenium to
function. In the reaction, glutathione is oxidized
to glutathione disulfide. In order to regenerate glutathione,
a series of enzymatic reactions occurs involving thiamin,
riboflavin, and niacin.
stress is the term used to describe a risk for damage
from oxygen radical reactions due to an imbalance
between oxidants and antioxidants. Oxidative stress
can lead to damage and disease. Table 1 present a
summary of the antioxidants vitamins and minerals
and their role in protection from the damage of oxidative
ANTIOXIDANT SUPPLEMENTS PREVENT CANCER AND HEART DISEASE?
and heart disease kill more people than any other
disease. Basic research indicates that oxidative stress
plays a role in these diseases, and animal research
has indicated potential for antioxidant vitamins to
help in preventing them. Here we will focus on studies
of the potential effects of antioxidant vitamins in
heart disease and cancer. Radicals may be involved
in the development of other diseases, but they will
be discussed only briefly because evidence for their
effect is more limited.
Epidemiological or population studies show generally
that dietary antioxidant vitamins have value in preventing
heart disease and cancer. In recent years several
placebo-controlled human studies targeting this effect
have been completed. The results of these specific
studies are encouraging but not in uniform agreement;
two large studies of the preventive benefit of beta
carotene that produced negative results have caused
considerable on this tissue.
epidemiological studies of dietary habits supported
the idea the antioxidants from dietary sources were
associated with a reduced risk of heart disease and
some cancers, especially lung cancer. These studies
rely on huge data collections from several study populations.
The Framingham Study is an example. Here a large segment
of the population of Framingham, Massachusetts, has
been followed for many years. Blood samples have been
periodically taken, questionnaires completed, diets
monitored, and the volunteers watched for changes
in health status. This study and many similar studies
from around the world consistently find that vegetable
and fruit consumption is related to the risk for coronary
heart disease and some cancers. That is, the more
fruits and vegetables you eat, the lower your risk.
At the high end of fruit and vegetable consumption
is related to the risk for coronary heart disease
and some cancers. That is the more fruits and vegetables
you eat, the lower your risk. At the high end of fruit
and vegetable intake, risk decreased by more than
50 percent compared to those eating the fewest fruits
What is it in the fruits and vegetables that may be
protective? When the diets are analyzed, intake of
Vitamin E, vitamin C, beta carotene, flavonoids, and
the mineral selenium are related to disease risk,
that is, the smaller the intake, the higher the risk.
While these studies suggest a strong benefit for antioxidant
vitamin intake, in one of their limitations that is
impossible to control for all confounding variables.
For example, it is possible that people eating a diet
high in vitamin E have a lower risk for heart disease
because they live a healthier lifestyle in general.
Studies of Vitamin Supplement Use
more recent large-scale human studies have looked
not only at diet but also at vitamin supplements taken
by the populations being studied. These results address
the issue of antioxidant vitamin supplement value
more directly, but there is still the question of
whether people who take supplements also have other
healthy lifestyle practices, which may account for
some of the observed results. Nevertheless, the value
of vitamin E supplements over and above the amount
obtained from a standard multivitamin now seems apparent
for help in the prevention of coronary disease.
For example, the Health Professionals Follow-up Study
has followed 51,529 male health professionals since
1986. Participants filled out detailed questionnaires
on their diet and supplement use. Based on the results
of four years of observation, and after controlling
for other risk factors, a lower risk of heart disease
was noted with increasing vitamin E dietary intake
in 39,910 men. Those at the high end of dietary intake
had a 36 percent smaller chance of developing heart
disease. Of special interest is the observation that
people taking vitamin E capsules in daily doses between
100 and 250 IU per day had a 46 percent lower risk
of heart disease compared to people who did not take
a supplement. Supplements had to be taken for at least
two years in order for them to have a protective effect.
Dietary carotene intake did not have a protective
effect, except in smokers and former smokers, nor
did total vitamin C intake. Multivitamin use was only
modestly protective and only in people who took multivitamins
for more than ten years.
The Nurses Health Study of 89,245 nurses followed
from 1980 to 1988 and showed that vitamin E had a
similarly strong protective effect against heart disease.
The greatest effect, a decrease in risk of almost
50 percent, was found in women who took more than
100 IU per day for at least two years, compared to
those who took no vitamin E supplement. Vitamin C
supplements and beta carotene intake were not protective.
Again, taking a multivitamin was only modestly protective.
The final example is a study of 11.178 elderly people,
ages 67 to 105 years, over a period of about ten years.
In this population, at high risk for death from heart
disease and cancer, vitamin E supplements had a striking
effect. People who took vitamin E supplements separate
from a multivitamin had a 37 percent lower risk of
death due to heart disease. The risk for death due
to cancer was 41 percent less in vitamin E users.
Those who used both vitamin E and vitamin C supplements
were somewhat better protected, with a 52 percent
smaller risk of disease.
There was a trend for people to benefit from the combination
of vitamins C and E in reducing cancer death, but
vitamin C use alone did not protect against death
from heart disease, cancer, or other causes. This
study is the best one to demonstrate an advantage
of taking both vitamin E and vitamin C. Multivitamin
use was not shown to be protective in this study.
previous studies provide reasonable evidence that
antioxidant vitamins, especially vitamin E, are useful
to help prevent heart disease. The evidence for protection
against cancer is weaker. More definitive proof of
protection is obtained from studies in which healthy
people without any evidence of disease take a placebo
or an antioxidant vitamin and are followed for a sufficient
length of time or until disease develops. These studies
are called primary prevention trials. As you might
imagine, primary prevention trials are expensive are
very difficult to conduct. As a result, these large
vitamin studies are generally funded by government
For example, the ATBC study followed 29, 133 Finnish
smokers for five to seven years. The volunteers received
either 20mg of beta carotene, 50 mg of vitamin E,
both vitamins, or an inactive placebo. Neither vitamin
alone nor the combination had a protective effect
against lung cancer. In fact, more lung cancers were
found in the beta carotene group. This study has been
criticized because of the low dose of vitamin E, because
of the fact that synthetic beta carotene was employed,
and because the smokers tested may have already had
cancer before they entered the study.
A second study (CARET) gave 18,314 smokers , former
smokers, or people exposed to asbestos either a combination
of 30 mg of beta carotene and 25,000 IU of vitamin
A or placebo. The study was stopped after four years
because, as with the ATBC study, a significant increase
in deaths due to lung cancer was seen in the beta
carotene/vitamin A group.
A third study, the Physicians' Health Study, was remarkable
in that 22,071 healthy physicians took either 50 mg
of beta carotene or placebo every other day and were
followed for twelve years. This study lasted longer
and studied a healthier population than the other
two. Beta carotene had neither a beneficial nor harmful
effect in this study.
Another study, published by the same group of Finnish
investigators who did the ATBC trial, looked at the
effect of 50mg of vitamin E on prostate cancer in
male smokers studies in ATBC. The researchers found
that men who took 50 mg of vitamin E for five to eight
years had a 23 percent smaller risk of developing
prostate cancer, and those who did get prostate cancer
were 41 percent less likely to die.
These large studies were disappointing for beta carotene
proponents. We cannot say much about vitamin E from
these studies because either it was not tested, the
dose used was too low, or the results, as in the prostate
cancer study, need to be confirmed.
secondary prevention trials looks at whether the treatment
will prevent a second occurrence of the disease being
studied in a group of people who have already experienced
the disease or who are at proven risk of the disease.
Vitamin E has been shown to provide a benefit in several
of these secondary prevention studies.
For example, 2,002 patients with heart disease were
given a placebo or 400 IU per day of vitamin E for
seventeen months. The vitamin E group had about 80
percent fewer nonfatal heart attacks, but the number
of fatal heart attacks was about the same for both
the E-treated and placebo groups.
Another study followed 156 men who had previous coronary
bypass surgery. Vitamin E, at doses over 100 IU per
day, reduced the worsening of heart disease compared
to placebo. No benefit was seen for vitamin C, for
multivitamin use, or for increased intake of dietary
In another study, patients with a previous colorectal
adenoma who had had their polyps removed received
either 400 IU of vitamin E with 1 gram of vitamin
C per day or an inactive placebo. There was no difference
between the placebo and vitamin E groups in the number
of patients who needed surgery to remove adenomas
after one year of treatment.
OF ANTIOXIDANT SUPPLEMENT BENEFIT IN OTHER DISEASES
older placebo-controlled studies, vitamin E has also
been shown to be of some help in people with intermittent
claudication, a painful condition due to poor circulation
in the limbs. The origin of this disease is the same
as a heart attack or stroke, atherosclerotic narrowing
of the arteries, so it is not surprising that vitamin
E can be helpful by virtue of its ability to reduce
plaque formation and to decrease platelet stickiness.
An exciting finding was that vitamin E treatment somewhat
slowed the rate of progression of Alzheimer's disease.
A total of 341 patients received a drug called slegiline,
a very high dose of vitamin, both or placebo. People
taking vitamin E experienced a greater delay in disease
progression than those taking selegiline alone or
placebo. More recently, a study at New York's Memorial
Sloan - Kettering Cancer Center found that one form
of vitamin C, dehydroascorbic acid, can get through
the blood-brain barrier, allowing large amounts of
vitamin C directly into brain tissue. The researchers
conclude that this technique may prove to be an important
therapeutic advance in treating Alzheimer's disease
and other conditions that result from damaged brain
cells. Clearly, more studies of vitamins E and C in
Alzheimer's disease are needed.
The final example has to do with the signs of aging.
Free-radical reactions progressively damage the immune
system as we get older. Investigators in Boston gave
doses of 60, 200, or 800 IU of vitamin E per day or
placebo to eighty0eight elderly subjects for four
months. Tests of immune function and antibody response
to vaccinations showed that vitamin E improved immune
function. The effect was generally better in the group
receiving 200 mg per day.
FOR TAKING ANTIOXIDANTS VITAMINS
antioxidant vitamins is a modest and inexpensive action
you can take to decrease the risks of cancer, heart
disease, and other conditions associated with aging.
The operative word here is modest. It is very important
to bear in mind that the largest benefit of vitamin
intake is smaller than the benefit that can be achieved
by making important lifestyle adjustments such as
stopping smoking, losing excess weight, and exercising.
While there is disagreement over the value of antioxidant
supplements, there is uniform agreement that a diet
high in vegetables and fruits and fiber is protective.
Your mother was right : Eat your vegetables.
Having improved your lifestyle, can you expect further
benefit by taking high doses of antioxidant vitamins?
We believe that the evidence says yes for vitamin
E, yes for vitamin C in combination with vitamin E,
and no for beta carotene; it's inconclusive for the
other antioxidant supplements. Here are our recommendations
for taking antioxidant vitamin supplements.
a multivitamin supplement with minerals every day.
Make sure the supplement contains selenium and folic
acid and 100 percent of the RDA for each of the
eleven vitamins. This product will provide all of
the vitamins you need for optimum antioxidant status,
except vitamins E and C, and will provide adequate
amounts of selenium. A generic product containing
100 percent of the RDA value of all vitamins and
selenium can be purchased for $4 to $8 per 100 tables.
This is inexpensive and safe insurance.
200 to 400 IU of natural vitamin E everyday. Higher
doses are not needed and lower doses have proven
to be less effective in human studies. Natural vitamin
E is absorbed and utilized better that the synthetic
form, though most clinical studies have used the
synthetic. The label should say d-alpha tocopherol.
If it does not or says d1-alpha tocopherol, it is
synthetic vitamin E.
250 to 500 mg of vitamin C every day. Generic, synthetic
vitamin C is fine. As discussed, the vitamin C works
together with vitamin E in removing damaging oxygen
radicals. Vitamin C without vitamin E does not appear
to be especially helpful.
Eat a few carrots everyday and increase your intake
of other vegetables. The carrot will provide a nice
mixture of carotenoids, and the other vegetables
will provide flavonoids shown to have protective
antioxidant properties. Avoid taking a synthetic
beta carotene supplement. Evidence from large human
clinical trials says it does nothing for, or might
be even harmful to, smokers or former smokers. Beta
carotene, at least the synthetic variety, is not
the magic ingredient in vegetables that provides
specialty antioxidant products. They are expensive
and often contain ingredients of unproven value.
give up on this program. Studies show that vitamin
E will benefit you only after you have taken it
for many months