US Pharm.
2008(12)(Student suppl):8-11.
An antioxidant, or a
free-radical scavenger, is a molecule capable of decreasing or preventing the
oxidation of other molecules. Oxidation reactions transfer electrons from a
substance to an oxidizing agent. During this process, some free-radicals are
produced, which starts chain reactions that damage animal cells. Antioxidants
slow down these chain reactions by removing free-radical intermediates and
eventually inhibit other oxidation reactions by being oxidized themselves.
Antioxidants often play the role of a reducing agent, e.g., thiols or
polyphenols.1
Antioxidants are compounds of
many different chemical structures and are classified into two broad
divisions, depending on whether they are soluble in water (hydrophilic) or in
lipids (hydrophobic). In general, water-soluble antioxidants react with
oxidants in the cell cytoplasm and the blood plasma, while lipid-soluble
antioxidants protect cell membranes from lipid peroxidation. These compounds
may be biosynthesized or obtained from the diet. Different antioxidants are
present at a wide range of concentrations in body fluids and tissues, with
some, such as glutathione or ubiquinone, mostly present within cells, while
others, such as uric acid, are more evenly distributed.1 In
general, they either prevent the formation of free-radicals or neutralize
those that are formed or repair the damage done by free-radicals. Using
antioxidant supplements has not been generally proven to replace the use of
natural or food-based antioxidants.
Oxidation reactions are
crucial for life, but they can also be damaging; hence, all live plants and
animals maintain a complex system of antioxidant enzymes such as catalase,
superoxide dismutase, and various peroxidases, as well as other antioxidants,
such as glutathione, vitamin C, and vitamin E. Low levels of antioxidants, or
inhibition of the antioxidant enzymes, cause oxidative stress and may damage
or kill cells.2
As oxidative stress might be
an important part of many human diseases, the use of antioxidants in medicine
is intensively studied, particularly as treatments for stroke and
neurodegenerative diseases; however, it is not known whether oxidative stress
is the cause or the consequence of disease. Antioxidants are widely used as
ingredients in dietary supplements in the hope of maintaining health and
preventing diseases such as cancer and coronary heart disease. Although some
studies have suggested antioxidant supplements have health benefits, other
large clinical trials did not detect major benefit for the formulations tested
and found that excess supplementation may be harmful. In addition to their
uses in medicine, antioxidants have many industrial uses, such as
preservatives in food and cosmetics and preventing the degradation of
materials such as rubber and gasoline.2
Free-Radicals
The atoms and
molecules that make up our bodies have one or more pairs of electrons in their
outer orbits. In the 1950s, scientists identified free-radicals as atoms or
molecules that are missing one of two electrons, thus forming the free-radical
molecules that seek to complete their structures. When a molecule or atom is
missing one of its electrons, it becomes unstable and will try to take another
electron from any other molecule in its immediate environment. If a
free-radical acquires an electron from the molecule next to it, then that
molecule or atom may become a free-radical. In turn, the next free-radical
attacks a molecule next to it, and so on. Thus, there is a chain reaction of
molecules that are desperately seeking completion, leaving severe damage in
their surroundings wherever an electron pair is broken. The free-radicals are
named troublemakers and originate mostly from reactive oxygen species.
The conversion of food to
energy in our bodies is accomplished in organelles--tiny structures within our
cells called mitochondria. The mitochondria may be thought of as little
furnaces that take food that has been broken down into its basic chemical
structure and then combine these chemicals with oxygen, producing water and
energy. The problem is that about 5% of the energy produced turns into
reactive oxygen species or free-radicals. In addition, free-radicals are
created in very high levels throughout the body whenever there is trauma,
infection, or inflammation. When we walk outside on a sunny day, the sunlight
immediately begins to trigger free-radical formation, which causes damage to
our skin and the tissue beneath it. Fortunately, nature has built-in-defense
mechanisms against free-radicals. These defense systems are antioxidants,
which prevent damage from oxygen.3
The Oxidative Stress
An imbalance
between the production of reactive oxygen species and biological systems'
ability to readily detoxify these reactive intermediates causes oxidative
stress. Many diseases, such as Alzheimer's, Parkinson's, some pathologies of
diabetes, rheumatoid arthritis, and other diseases caused by
neurodegeneration, are believed to develop due to oxidative stress. In many of
these cases, it is unclear whether oxidants trigger the disease or whether
they are produced as a consequence of the disease and cause the disease
symptoms. It is known that low-density lipoprotein (LDL) oxidation appears to
trigger the process of atherogenesis, which results in atherosclerosis and
finally cardiovascular diseases.4
As mentioned earlier, while
the vast majority of organisms require oxygen for their existence, oxygen is
also a highly reactive molecule that damages living organisms by producing
reactive oxygen species. Consequently, organisms contain a
complex network of antioxidant and enzyme systems that work together to
prevent oxidative damage to cellular components such as DNA, proteins, and
lipids. In general, antioxidant systems either prevent these reactive species
from being formed or remove them before they can damage vital components of
the cell.
Some of the most important
reactive oxygen species that are produced in cells are hydrogen peroxide (H2O2),
hypochlorous acid (HClO), and free-radicals such as the hydroxyl radical (-OH)
and the superoxide anion (O2-). All of these are by-products of
several steps in the body's electron transfer mechanisms. The hydroxyl radical
is very unstable and will react rapidly and nonspecifically with most
biological molecules. These oxidants can damage cells by starting chemical
chain reactions such as lipid peroxidation or by oxidizing DNA or proteins.
Damage to DNA can cause mutations and possibly cancer if not reversed by DNA
repair mechanisms, while damage to proteins causes enzyme inhibition,
denaturation, and protein degradation.
Plants can also neutralize
reactive oxygen species that are produced during photosynthesis by the
involvement of their carotenoids in photoinhibition. Carotenoid antioxidants
in turn react with overreduced forms of the photosynthetic reaction centers to
prevent the production of reactive oxygen species.
A low-calorie diet extends
median and maximum lifespan in many animals. This effect may involve a
reduction in oxidative stress. Diets rich in fruit and vegetables, which are
high in antioxidants, promote health and reduce the effects of aging; however,
antioxidant vitamin supplementation has no detectable effect on the aging
process, so the effects of fruit and vegetables on aging may be unrelated to
their antioxidant content. One reason for this might be the fact that
consuming antioxidant molecules such as polyphenols and vitamin E produces
other metabolic changes, so it may be that these other nonantioxidant effects
are important in human nutrition.5
Antioxidants' Cons and Pros
There is some
evidence that antioxidants might help prevent diseases such as macular
degeneration, suppressed immunity due to poor nutrition, and
neurodegeneration. A number of observations suggest that antioxidants might
help prevent these conditions; however, despite the clear role of oxidative
stress in cardiovascular disease, controlled studies using antioxidant
vitamins have observed no major reduction in either the risk of developing
heart disease or the rate of progression of existing disease. As a result,
these effects might be the result of other substances in fruit and vegetables
(possibly flavonoids), or a complex mix of substances may contribute to the
better cardiovascular health of those who consume more fruit and vegetables.
It is also believed that
oxidation of LDL in the blood contributes to heart disease, and initial
observational studies found that people taking Vitamin E supplements had a
lower risk of developing heart disease. Consequently, at least seven large
clinical trials were conducted to test the effects of antioxidant
supplementation with vitamin E, in doses ranging from 50 to 600 mg per day.
Interestingly, none of these trials found a statistically significant effect
of vitamin E on overall number of deaths or on deaths due to heart disease.
Therefore, it is not clear if the doses used in these trials or in most
dietary supplements are capable of producing any significant decrease in
oxidative stress.6
Many nutraceutical and health
food companies now sell formulations of antioxidants as dietary supplements,
and these are widely used in industrialized countries. These supplements may
include specific antioxidant chemicals, such as resveratrol (from grape
seeds); combinations of antioxidants, like the ACES products that contain beta
carotene (provitamin A), vitamin C, vitamin E, and Selenium;
or herbs that contain antioxidants, such as green tea. Although some levels of
antioxidant vitamins and minerals in the diet are required for good health,
there is some doubt as to whether antioxidant supplementation is beneficial
and, if so, which antioxidant(s) are beneficial and in what amounts.
The brain is uniquely
vulnerable to oxidative injury due to its high metabolic rate and elevated
levels of polyunsaturated lipids, the target of lipid peroxidation.
Consequently, antioxidants are commonly used as medications to treat various
forms of brain injury. Hence, superoxide dismutase mimetics, sodium
thiopental, ascorbic acid, and propofol are used to treat reperfusion injury
and traumatic brain injury. These compounds appear to prevent oxidative stress
in neurons and prevent apoptosis and neurological damage.7
Total Antioxidant Capacity
Measurement of
antioxidants is not a straightforward process, as this is a diverse group of
compounds with different reactivities to different reactive oxygen species. In
food science, the oxygen radical absorbance capacity (ORAC) has become the
current industry standard for assessing the antioxidant strength of whole
foods, juices, and food additives. Other measurement tests are the
Folin-Ciocalteu reagent and the Trolox Equivalent antioxidant capacity assay.
In medicine, a range of different assays are used to assess the antioxidant
capability of blood plasma. Of these, the ORAC assay may be the most reliable.
Different foods have different
quantities of antioxidants, and the total amount can be measured by chemical
means. The total antioxidant capacity (TAC) is expressed in micromoles per 100
grams of food and equals Lipophilic-ORAC + Hydrophilic-ORAC. Different
measurement methods, however, yield different results, and these are only
relevant when used comparatively within the same batch of food. TAC is a
useful quantitative analytical measure of antioxidant content, but it lumps
together the good, the bad, and the positively harmful compounds loosely
classified as antioxidants.
The Michelin Star Guide has
been used to rank individual antioxidants (TABLE 1). This rating system
is being extended to antioxidant classes and food items. No individual
antioxidant has been awarded more than three stars. It will require
combinations, metabolites, or the initiation of physiological antioxidants to
achieve a four- and five-star ranking.8
Antioxidants and Physical Activity
During the peak of
exercise, oxygen consumption can increase by a factor of more than 10. This
leads to a large increase in the production of oxidants and results in damage
that contributes to muscular fatigue during and after exercise. The
inflammatory response that occurs after heavy exercise is also associated with
oxidative stress, especially in the 24 hours after an exercise session. The
immune system response to damage done by exercise peaks two to seven days
after exercise, the period during which the results of exercise to fitness is
greatest. During this process, some of the body mechanisms try to remove
damaged tissues, and excessive antioxidant levels have the potential to
inhibit recovery and adaptation mechanisms.
The evidence for benefits from
antioxidant supplementation in vigorous exercise is mixed. There is strong
evidence that one of the adaptations resulting from exercise is a
strengthening of the body's antioxidant defenses, particularly the glutathione
system, to deal with the increased oxidative stress.9 It is
possible that this effect may be to some extent protective against diseases
that are associated with oxidative stress, which would provide a partial
explanation for the lower incidence of major diseases and better health of
those who undertake regular exercise.
However, no benefits to
athletes are seen with vitamin A or E supplementation. For example, despite
its key role in preventing lipid membrane peroxidation, six weeks of vitamin E
supplementation had no effect on muscle damage in serious runners. Although
there appears to be no increased requirement for vitamin C in athletes, there
is some evidence that vitamin C supplementation increases the amount of
intense exercise that can be done and reduces muscle damage from heavy
exercise. Other studies found no such effects, however, and some research
suggests that supplementation with amounts as high as 1,000 mg inhibits
recovery.10
Adverse Effects
Nonpolar
antioxidants such as eugenol, a major component of oil of cloves, have
toxicity limits that can be exceeded with the misuse of undiluted essential
oils. Toxicity associated with high doses of water-soluble antioxidants such
as ascorbic acid is less of a concern, as these compounds can be excreted
rapidly in urine. Very high doses of some antioxidants may have serious
long-term effects. The Beta-Carotene and Retinol Efficacy Trial (CARET) study
of patients with lung cancer found that smokers given supplements containing
beta-carotene and vitamin A had increased rates of lung cancer. Subsequent
studies also confirmed these adverse effects.11
While antioxidant
supplementation is widely used in attempts to prevent the development of
cancer, it has been proposed that antioxidants may, paradoxically, interfere
with cancer treatments. This was thought to occur since the environment of
cancer cells causes high levels of oxidative stress, making these cells more
susceptible to the further oxidative stress induced by treatments. As a
result, by reducing the redox stress in cancer cells, antioxidant supplements
in very large doses were thought to decrease the effectiveness of radiotherapy
and chemotherapy.12 This concern appears unfounded, however,
because multiple clinical trials have reported that antioxidants are either
neutral or beneficial in cancer therapy.11
Some antioxidants are made in
the body but are not absorbed from the intestine. One example is glutathione,
which is made from amino acids. As any glutathione in the gut is broken down
to free cysteine, glycine, and glutamic acid before being absorbed, even large
oral doses have little effect on the concentration of glutathione in the body.9
Coenzyme Q-10 is also poorly absorbed from the gut and is made in humans
through the mevalonate pathway.13
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2. Imlay J. Pathways of oxidative damage. Annu Rev Microbiol. 2003;57:395-418.
3. Krieger-Liszkay A. Singlet oxygen production in photosynthesis. J Exp Bot.2005;56:337-346.
4. Cherubini A, Vigna G, Zuliani G, et al. Role of antioxidants in atherosclerosis: epidemiological and clinical update. Curr Pharm Des. 2005;11:2017-2032.
5. Sohal R. Role of oxidative stress and protein oxidation in the aging process. Free Radic Biol Med. 2002;33:37-44.
6. Herrera E, Barbas C. Vitamin E: action, metabolism and perspectives. J Physiol Biochem. 2001;57:43-56.
7. Duarte TL, Lunec J. Review: when is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C. Free Radic Res. 2005;39:671-686.
8. Total Antioxidants of Common
Foods. www.naturalantioxidants.org/Total_
Antioxidants.html.
9. Hayes J, Flanagan J, Jowsey I. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45:51-88.
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11. Antioxidants and Cancer Prevention: Fact Sheet. National Cancer Institute. Accessed February 27, 2007.
12. Moss R. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr Cancer Ther. 2006;5:63-82.
13. http://en.wikipedia.org/wiki/Antioxidant.
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