Antioxidant Nutrients: Current Dietary

Recommendations and Research Update

from Journal of the American Pharmaceutical Association

June H. McDermott

Abstract and Introduction

Abstract

Objective: To review the importance of antioxidant nutrients in the

maintenance of health and the prevention and treatment of disease, with
a focus on data pertaining to vitamin C, vitamin E, selenium, and
carotenoids. A secondary objective was to discuss the new Dietary
Reference Intakes released by the Institute of Medicine (IOM) for these
nutrients.
Data Sources: IOM reports on the use of antioxidant vitamins were
reviewed for nutrient recommendations. In addition, a MEDLINE search
was performed to identify recent research and review articles on the
topic, which were analyzed to identify key research findings in the area.
Data Synthesis: The review discusses the biologic processes of
oxidation reactions and antioxidants in biologic systems, provides an
overview of information on selected antioxidant nutrients, and explores
their role in the prevention and treatment of cancer, cardiovascular
disease, ocular disorders, and respiratory disorders.
Conclusion: There appear to be significant health benefits from dietary
antioxidants, as can be found in fruits and vegetables. Some prospective
assessment of the effect of supplemental antioxidants also suggests
benefit, especially for vitamin E; however, there are conflicting results in
this area. Overall, it appears that antioxidant nutrients, especially those
from food sources, have important roles in preventing pathogenic
processes related to cancer, cardiovascular disease, macular
degeneration, cataracts, and asthma, and may enhance immune
function.

Introduction

It is estimated that 40% of the U.S. population takes vitamin

supplements, and recently much public and scientific interest has been
directed toward antioxidants in particular.[1]
Antioxidant nutrients are believed to play a role in the prevention and
treatment of a variety of chronic diseases, ranging from asthma to
cardiovascular disease (CVD) and cancer. The proposed mechanism by
which antioxidants protect cells from oxidative stress is by scavenging
free radicals and halting lipid peroxidation chain reactions, which can
cause DNA damage.[2]

In light of new research on the importance of these vitamins to overall

heath, the Institute of Medicine (IOM) recently released new dietary
guidelines for intake of the antioxidant nutrients vitamin C, vitamin E,
carotenoids, and selenium. In addition, a variety of other nutrients are
believed to be involved in antioxidant processes.

This article reviews antioxidant processes in biologic systems and

properties of selected antioxidant nutrients. In addition, a summary of the
benefits of antioxidant nutrients in enhancing immune function and in the
prevention and treatment of cancer, CVD, and certain ocular and
respiratory disorders is provided. Finally, counseling tips are provided for
pharmacists who may be questioned about the health benefits of
antioxidant supplements.

Section 1 of 7

June H. McDermott, MS Pharm, MBA, FASHP, is clinical assistant

professor, School of Pharmacy, University of North Carolina, Chapel Hill.

Correspondence: June H. McDermott, MS Pharm, MBA, FASHP,

University of North Carolina, School of Pharmacy, CB #7360, Beard Hall,
Chapel Hill, NC 27599. Fax: 919-966-9428. E-mail:
June_McDermott@unc.edu.

J Am Pharm Assoc 40(6):785-799, 2000. © 2000 American Pharmaceutical

Association

Antioxidant Processes
Two forms of chemical reactions, oxidation and reduction, occur widely in
nature. Oxidation is the loss of electrons, and reduction is the gain of
electrons. Oxidation and reduction reactions always occur in pairs, i.e.,
when one atom or molecule is oxidized, another is reduced. Highly
reactive molecules can oxidize molecules (i.e., remove electrons from
molecules) that were previously stable, and may cause them to become
unstable species, such as free radicals.
A free radical is a chemical species with an unpaired electron that can be
neutral, positively charged, or negatively charged. Although a few stable
free radicals are known, most are very reactive. In free radical chain
reactions, the radical product of one reaction becomes the starting
material for another, propagating free radical damage.

There are three steps to free-radical chain reaction: initiation,

propagation, and termination. In the initiation step, free radicals are
formed from molecules that readily give up electrons, such as hydrogen
peroxide. In the propagation steps, the chain-carrying radicals are
alternately consumed and produced. In the termination steps, radicals are
destroyed.[3] Thus, without termination by an agent such as an
antioxidant, a single free radical can damage numerous molecules.

There are four common oxygen metabolites in biologic systems that are
free radicals: superoxide anion (O2- ), hydrogen peroxide (H2O2), hydroxyl
radical (OH ), and singlet oxygen (1O2). These free radicals can be
generated via a number of mechanisms, including normal physiologic
processes and processes resulting from external factors. For example,
singlet oxygen is generated by photosensitization reactions wherein a
molecule absorbs light of a given wavelength, exciting the molecule. This
excited molecule transfers the increased energy to molecular oxygen,
creating singlet oxygen, which then can attack other cell components. It
appears that the primary function of carotenoids, an important class of
antioxidants, is to scavenge free radicals, particularly singlet oxygen
produced by photosensitization.[4]

A certain amount of oxidative function is necessary for proper health. For

example, oxidation processes are used by the body's immune systems to
kill microorganisms.[4] Sometimes, however, the level of toxic reactive
oxygen intermediates (ROI) overcomes the antioxidant defenses of the
host, resulting in an excess of free radicals and a state called oxidative
stress. These free radicals can induce local injury by reacting with lipids,
proteins, and nucleic acids.[5] The interaction of free radicals with cellular
lipids leads to membrane damage and the generation of lipid peroxide
byproducts.[5]

Cells contain a number of antioxidants that have various roles in

protecting against free radical reactions. The major water-soluble
antioxidant metabolites are glutathione (GSH) and vitamin C, which
reside primarily in the cytoplasm and mitochondria. Many water-soluble
enzymes also catalyze these reactions. Glutathione peroxidase catalyzes
the reaction between GSH and hydrogen peroxide to form water and
oxidized glutathione, which is stable.[4]
Vitamin E and the carotenoids are the principal lipid-soluble antioxidants.
Vitamin E is the major lipid-soluble antioxidant in cell membranes that
can break the chain of lipid peroxidation. Therefore, theoretically, it is the
most important antioxidant in preventing oxidation of these fatty acids.
Vitamin E is recycled by a reaction with vitamin C.[4]

Despite the actions of antioxidant nutrients, some oxidative damage will

occur, and accumulation of this damage throughout life is believed to be
a major contributing factor to aging and disease.[4]

Dietary Reference Intakes

IOM recently updated nutritional requirements for the antioxidant
nutrients (vitamin C, vitamin E, carotenoids, and selenium), as well as
other nutrients. In the past, Recommended Dietary Allowances (RDAs)
were used in the United States and Recommended Nutrient Intakes
(RNIs) were used in Canada. Since the last review of these guidelines in
1989 and 1990, respectively, new data have emerged reflecting dietary
requirements of food components and their role in maintaining health.
Currently available data address topics ranging from classical nutritional
deficiencies, such as scurvy, to the reduction of risk of chronic diseases,
such as cancer and CVD. This expansion in available data led to the
need to develop updated recommendations.

The updated recommendations, developed in a collaboration between the

United States and Canada, incorporate three types of values: the
estimated average requirement (EAR), RDA, and the Tolerable Upper
Intake Level (UL). Collectively, these values are referred to as Dietary
Reference Intakes (DRIs) (Table 1).

The EAR is the intake value that is estimated to meet the requirements of
a defined indicator of adequacy in 50% of the population (note that this
means that the needs of 50% of the population are not being met). The
RDA is the dietary intake level that is sufficient to meet the nutrient
requirements of nearly all individuals in the group. However, IOM has
concluded that the data supporting the benefits of these nutrients in
preventing chronic disease are incomplete. Thus, these requirements are
based on other markers of deficiency (e.g., prevention of scurvy).

The availability of nutrients and food components as dietary supplements

has resulted in the need to establish ULs to help consumers avoid
possible toxicity (Table 2). ULs are established on the basis of both
available data and scientific judgment. The UL is not intended to be a
recommended level of intake, but represents the highest level of intake
that is unlikely to have any adverse health effects in most individuals. It is
important to note that the UL is not meant to apply to individuals receiving
supplements under medical supervision, and should not be used to limit
doses investigated in clinical trials.[6]

DRIs for antioxidant nutrients were developed by considering the roles of

antioxidant nutrients in decreasing the risk of diseases, including chronic
diseases and other conditions, and by interpreting the current data on
intakes in the United States and Canada.

Antioxidant Nutrients
According to IOM, a dietary antioxidant is defined as "a substance in
foods that significantly decreases the adverse effects of reactive species,
such as reactive oxygen and nitrogen species, on normal physiological
function in humans."[6]This article focuses on the antioxidant nutrients
vitamin C, vitamin E, selenium, and the carotenoids. A multitude of other
nutrients, including minerals such as copper, manganese, and zinc,
flavonoids (such as grape seed extract and phenols found in green tea),
and coenzyme Q10, also possess antioxidant properties but are beyond
the scope of this review.

Vitamin C

Role in the Body and Consequences of Deficiency The primary

function of vitamin C (ascorbic acid) is the production of collagen, which
forms the basis for connective tissue in bones, teeth, and cartilage. It also
plays an important role in wound healing, immunity, and the nervous
system, and acts as a water-soluble antioxidant.

Because vitamin C is water soluble, its antioxidant functions take place in

aqueous body compartments. It also helps protect low-density lipoprotein
cholesterol (LDL-C) against free radical damage. As an antioxidant, it
helps protect against cancer,[7] CVD,[8-10] and certain effects of aging.[11]

Severe deficiency of vitamin C leads to scurvy, which includes symptoms

of bleeding gums, joint pain, easy bruising, dry skin, fluid retention, and
depression. Marginal deficiencies may play a role in the development of
cancer,[12,13] CVD,[14-16]hypertension,[17] decreased immunity, diabetes,[18] and
cataracts.[19]

Recommended Daily Allowances The RDA for vitamin C is 75 mg/day

for women and 90 mg/day for men. Smokers require an additional 35
mg/day due to increased oxidative stress and other metabolic
differences. The UL for vitamin C is 2,000 mg/day.[6]

Some researchers advocate dosages of vitamin C that exceed the RDA.

[20]
One study found that steady-state plasma concentrations of vitamin C
in healthy volunteers could be achieved with doses of 200 mg/day and
claimed that this was the optimal dose.[21] Furthermore, this study found
that while doses as high as 1,000 mg/day were safe, there was no
increase in bioavailability from doses above 400 mg/day.[21] However, it
remains possible that higher vitamin C intakes may be beneficial in the
treatment or prevention of certain diseases, particularly cancer and
respiratory disorders.

Food Sources Important sources of vitamin C include citrus fruits,

strawberries, kiwifruit, papaya, and vegetables such as red peppers,
broccoli, and brussels sprouts. Vitamin C can easily be destroyed during
cooking and storage; therefore, food handling and preparation can have a
significant effect on vitamin C content.

Risks at High Doses Vitamin C is relatively safe at high doses, but

intake of doses higher than 2 grams/day may result in diarrhea, nausea,
stomach cramping, excess urination, and skin rashes.[22] More recently,
4 grams/day has been said to be well-tolerated and safe, except in some
patients with renal dysfunction.[1]

In rare cases, daily 2 gram doses of vitamin C have been associated with
kidney stones.[23] In one study, vitamin C intake of 500 mg to 2 grams was
associated with an increase in urinary oxalate, suggesting a possible
mechanism.[24] However, not all studies have demonstrated this effect.[25,26]
For example, one study found that in 10 healthy subjects who had been
ingesting 3 to 10 grams of vitamin C for at least 2 years, the plasma
concentration of oxalic acid was within the normal range.[25] This study
also found that administration of 10 grams/day of vitamin C had no
significant effect on oxalate excretion in 5 of 6 tested subjects.[25] In
addition, a 14-year prospective follow-up study failed to demonstrate an
association between vitamin C intake and kidney stones.[27] Levine et al.[20]
concluded that vitamin C intake of greater than 1 gram/day increases
oxalate excretion without clinical consequence in normal healthy
individuals, but could lead to adverse consequences in those with
underlying renal disease.

Interactions with Other Nutrients and Drugs Vitamin C increases iron

absorption in the gastrointestinal (GI) tract but does not appear to affect
body iron stores.[28] It also acts synergistically with other antioxidant
vitamins. Dietary needs of vitamin C are increased by smoking,
pollutants, aspirin, alcohol, estrogen, antibiotics, and corticosteroids. It
may also interact with various laboratory tests, causing false readings.[1]

Vitamin E
Vitamin E is the name given to a group of eight fat-soluble compounds:
-, -, -, and -tocopherol, and -, -, -, and -tocotrienol. The most
abundant form of vitamin E is -tocopherol, and this is the only form that
is active in humans.[6] However, research suggests that the mixed forms
found in food may be more beneficial than the isolated -tocopherol form
that is used in some supplements.[29]

Vitamin E supplements are available in natural forms from soybean or

wheat germ oil, indicated by a "d" prefix (also referred to as the
stereoisomer RRR-a tocopherol), and synthetic forms manufactured from
purified petroleum oil, indicated by a "dl" prefix (which includes eight
stereoisomers of -tocopherol, 4 2R-stereoisomers and 4 2S-
stereoisomers). The 2S-stereoisomers of -tocopherol are not maintained
in human plasma or tissues, and therefore are not active in humans.
[6]
Mixed tocopherol supplements are also available. In some supplements,
vitamin E is esterified (e.g., -tocopherol acetate or -tocopherol
succinate) to extend its shelf life. These forms are hydrolyzed and
absorbed as efficiently as -tocopherol.[30]

Role in the Body and Consequences of Deficiency Unlike other

vitamins, which are involved in metabolic reactions, it appears that the
primary role of vitamin E is to act as an antioxidant. Vitamin E is
incorporated into the lipid portion of cell membranes and other molecules,
protecting these structures from oxidative damage and preventing the
propagation of lipid peroxidation.[6] Vitamin E appears to have protective
effects against cancer,[31] heart disease,[32] and complications of diabetes.
[32]

As an antioxidant, vitamin E plays a protective role in many organs and

systems. Vitamin E is necessary for maintaining a healthy immune
system,[33] and it protects the thymus and circulating white blood cells
from oxidative damage. Also, it may work synergistically with vitamin C in
enhancing immune function.[34] In the eyes, vitamin E is needed for the
development of the retina and protects against cataracts and macular
degeneration.[35]

Vitamin E deficiency is rare, and occurs mostly in people with chronic

liver disease and fat malabsorption syndromes, such as celiac disease
and cystic fibrosis. It can lead to nerve damage, lethargy, apathy, inability
to concentrate, staggering gait, low thyroid hormone levels, decreased
immune response, and anemia. Marginal vitamin E deficiency may be
much more common and has been linked to an increased risk of CVD
and cancer.[36]

Recommended Daily Allowances Of the fatty acids, polyunsaturated

fatty acids are most likely to undergo oxidation in the presence of oxygen
or oxygen-derived radicals. The necessary amount of vitamin E depends
on the amount of polyunsaturated fatty acids in the diet. The greater the
amount of these fats in the diet, the greater the risk that they will be
damaged by free radicals and exert harmful effects. An -tocopherol to
polyunsaturated fatty acid ratio of 0.4 is considered desirable.[32] Amounts
of vitamin E are measured in milligrams of -tocopherol equivalents (mg
of TE); however, international units (IU) was the previous standard and is
still sometimes used. Conversion factors for synthetic and natural forms
of vitamin E are listed in Table 3. The RDA for both men and women is
15 mg/ day of -a TE; however, many studies showing protective effects
against chronic diseases have used higher doses. The UL for vitamin E is
1,000 mg/day of -TE.[6,37] Because it is impossible to obtain a high intake
of vitamin E without consuming a high-fat diet, use of vitamin E
supplements is often recommended.[32]

Food Sources The best sources of vitamin E are certain vegetable oils
(including wheat germ oil, hazelnut oil, sunflower oil, and almond oil),
wheat germ, whole grain cereals, and eggs.

Risks at High Doses According to IOM, vitamin E is relatively safe at

doses as high as 1,000 mg/day.[6]Short-term administration of doses as
high as 3,200 mg/day has not been found to be toxic, but adverse effects
have been reported with extended intake of 1,100 to 2,100 mg/day of -
tocopherol.[6,38]Reported adverse effects include increased risk of
bleeding, diarrhea, abdominal pain, fatigue, reduced immunity, and
transiently raised blood pressure. Some research suggests that very high
doses may be pro-oxidant (i.e., acting as free radicals), especially in
smokers.[39]

Interactions with Other Nutrients and Drugs Vitamin E exerts

antioxidant effects in combination with other antioxidants, including -
carotene, vitamin C, and selenium. Vitamin C can restore vitamin E to its
natural reduced form. Vitamin E is necessary for the action of vitamin A
and may protect against some of the adverse effects of excessive vitamin
A. Because inorganic iron destroys vitamin E, the two should not be
taken simultaneously. Cholestyramine, mineral oil, and alcohol may
reduce the absorption of vitamin E.[37]

Based on the results of a single case report, there has been concern that
coadministration of vitamin E with anticoagulants (e.g., warfarin) may
enhance their effects.[37,40] However, a randomized clinical trial that
investigated the effects of vitamin E administration in patients on long-
term warfarin therapy found no significant change, and the researchers
concluded that vitamin E may safely be given to patients receiving
warfarin.[41]

Carotenoids
Carotenoids (also referred to as carotenes) are a group of more than 600
highly colored plant compounds; however, only 14 have been identified in
human blood and tissue.[42]The most prevalent carotenoids in North
American diets include -carotene, -carotene, lycopene, lutein,
zeaxanthin, and -cryptoxanthin. Only three ( -carotene, -carotene, and
-cryptoxanthin) are converted to vitamin A and considered provitamin A
carotenoids.[6]

Role in the Body and Consequences of Deficiency The only specific

effect of carotenoids in humans is to act as a source of vitamin A in the
diet, but they also have important antioxidant actions. The latter are
based on the caretenoids' ability to quench singlet oxygen and trap
peroxyl radicals, thereby preventing lipid peroxidation.[42] As a result,
carotenoids protect against the development of cancer, CVD, and ocular
disorders. Carotenoids also affect cell growth regulation and gene
expression. Diets low in carotenoids may lead to increased risk of cancer
and heart disease. Lycopene is the most potent antioxidant for quenching
single oxygen and scavenging free radicals.[43]

Recommended Daily Allowance Numerous studies have suggested

that higher blood concentrations of -carotene and other carotenoids are
associated with lower risk of several diseases. However, IOM has
concluded that this evidence cannot be used to establish a requirement
for -carotene or total carotene intake, because these effects may be the
result of other compounds found in carotenoi -rich foods or may be
related to behaviors correlated with increased fruit and vegetable
consumption.[6] Therefore, currently there are no DRIs for carotene intake,
as it is believed that the current state of research on these nutrients is not
strong and consistent enough to support any recommendations. An
intake of -carotene 6 mg is needed to meet the vitamin A RDA of 1,000
mcg retinol equivalents (RE).[37] (RE is a measurement of vitamin A intake
that allows for comparison of different forms of the vitamin.) One IU of
vitamin A is equivalent to -carotene 0.6 mcg.[44] Due to insufficient data
demonstrating a threshold above which adverse events will occur, no UL
has been set for any carotenoid.[6]

Food Sources Primary sources of -carotene include carrots, sweet

potatoes, pumpkin, cantaloupe, pink grapefruit, spinach, apricots,
broccoli, and most dark green leafy vegetables. -carotene is not
destroyed by cooking.

Lycopene is abundant in tomatoes, carrots, green peppers, and apricots.

Lycopene is concentrated by food processing and therefore may be
found in high concentrations in foods such as processed tomato products
(e.g., spaghetti sauce and tomato paste). Lutein is found in green plants,
corn, potatoes, spinach, carrots, and tomatoes, and zeaxanthin is found
in spinach, paprika, corn, and fruits.

Risks at High Doses Carotenoids are believed to be safe at fairly high

doses. Some areas of skin may become orange or yellow in color
(carotenodermia) if high doses of -carotene (30 mg/day or greater) are
taken for long periods, but will return to normal when intake is reduced.[6]
This effect can be used therapeutically in clinical practice to treat patients
with erythropoietic photoporphyria (a photosensitivity disorder). Such
patients have been treated with doses of approximately 180 mg/day
without reports of toxic effects.[6]

Supplements of synthetic -carotene have enhanced bioavailability and

have been associated with an increased risk of lung cancer; these
findings are discussed in more detail below under the section on cancer.

Interactions with Other Nutrients Carotenoids require bile acids to be

absorbed. Conversion of carotenoids to vitamin A requires protein,
thyroid hormone, zinc, and vitamin C.

Selenium

Role in the Body and Consequences of Deficiency The most

important antioxidant mineral is selenium. Selenium is essential for the
function of the antioxidant enzyme glutathione peroxidase, and it is also
important for healthy immune and cardiovascular systems. Keshan
disease, the only disease known to be linked to selenium deficiency, is a
cardiomyopathy found primarily in children. It is only known to occur in
some areas of
China where the soil is severely deficient in selenium, resulting in low
selenium intake. Low selenium intake has been also associated with
cancer,[45-47] heart disease,[48] arthritis,[49] asthma,[50] and cataracts.[51]

Recommended Daily Allowance The RDA of selenium for men and

women is 55 mcg/day and the UL is 400 mcg/day.

Food Sources Dietary intakes depend on the content of the soil where
plants are grown or where animals are raised. Good sources of selenium
include organ meats and seafood. Because plants do not require
selenium, concentrations of this antioxidant in plants vary greatly, and
food tables that list average selenium content are unreliable for plant
foods. In the United States and Canada, the food distribution system
ensures that regions with low selenium concentrations in the soil do not
have low selenium dietary intakes.[6]

Risks at High Doses The UL for selenium is 400 mcg per day; toxicity is
noted at mean doses greater than 800 mcg/day, with a 95% confidence
limit of 600 mcg/day.[52] Doses above this range result in early symptoms
of selenosis, including fatigue, irritability, and dry hair.[6,53,54] More
advanced symptoms include dental caries, hair loss, loss of skin
pigmentation, abnormal nails, vomiting, nervous system problems, and
bad breath.[53]

Interactions with Other Nutrients The combination of selenium and

vitamin E seems to have synergistic effects for the treatment of heart
disease, ischemia, and cancer. Vitamin C may also produce synergistic
effects, but large doses of vitamin C may result in decreased absorption.
[37]

Antioxidants in Health and Disease

At high levels, reactive oxygen species can be damaging to cells and
may contribute to cellular dysfunction and disease. Thousands of studies
have investigated the effects of antioxidant nutrient intake on immune
function and the risk of chronic diseases, including cancer, respiratory
disorders, and CVD. Because a complete review of the entire database of
research is beyond the scope of this article, this section focuses on
results from large, epidemiologic studies and intervention trials, and also
discusses a few studies that found an inverse association, and other
salient findings.

Immune Function

Antioxidant nutrients are often thought of as enhancing immune function.

Vitamin C, in particular, is generally perceived as useful in the prevention
and treatment of the common cold. Some evidence does support a role of
vitamin C, vitamin E, and carotenoids in enhancing immunity.

Vitamin C has been found to affect the human immune response, with
increased antimicrobial and natural killer cell activities, lymphocyte
proliferation, chemotaxis, and delayed dermal sensitivity. Studies have
involved pharmacologic doses of vitamin C (200 mg/day to 6 grams/day
in addition to dietary intake); therefore, the effect does not appear to
apply to nutritional intake of vitamin C from food alone.[6]

There has been much interest in the use of pharmacologic doses of

vitamin C to prevent or treat the common cold, and some studies have
reported beneficial results. Treatment of the common cold with vitamin C
is associated with reduced duration of cold symptoms.[55] Large
systematic reviews have concluded that supplementation with large
doses (1 gram/day or greater) of vitamin C does not reduce the incidence
of the common cold.[6,55] However, some reviewers have suggested that
vitamin C 600 mg/day to 1 gram/day is beneficial for preventing colds in
individuals under heavy physical stress.[56] For example, marathon
runners were found to have significantly fewer post-race upper
respiratory infections after treatment with vitamin C 600 mg/day.[57]

Supplemental vitamin E has been found to improve immune function in

older adults. Vitamin E 200 mg/day was found to enhance certain indexes
of T-cell-mediated function in healthy individuals > 65 years of age.[33] At
100 mg/day, vitamin E was found to enhance cellular immune function in
individuals 65 to 80 years of age.[58] Whether or not increases of vitamin E
intake are beneficial for younger adults remains to be proven.[6]

Carotenes also are associated with enhancing immune function;

however, as a provitamin to vitamin A, these results may be attributed to
vitamin A, which is known to enhance immunity.[6,37,59] Some research,
however, does demonstrate immune-enhancing properties that can be
attributed to the -carotene molecule itself.[60]

Cancer

Mounting evidence demonstrates that nutritional factors can influence risk

for the development of cancer, prognosis following the diagnosis of
cancer, and quality of life during cancer treatment (Table 4). A great deal
of epidemiologic evidence indicates that diets rich in fruits and vegetables
are associated with a lower risk of incurring a number of common
cancers, particularly those of the lung, oral cavity, pharynx, larynx, and
cervix.[6] However, there is more limited support for the use of individual
chemical entities found in supplements.[6]

Primary Prevention Research has shown that low serum concentrations

of -carotene increase the risk of certain types of cancer, including those
of the breast, lung, stomach, prostate, colon, ovary, and cervix.[37]For
nonsmoking men and women, dietary -carotene, raw fruits and
vegetables, and vitamin E supplements have been found to have a
protective effect against lung cancer.[61]

One study found low serum concentrations of -carotene in patients with

cancers of the lung, stomach, esophagus, small intestine, cervix, and
uterus; the strongest findings were for lung cancer. In general, the cancer
sites associated with low serum -carotene concentrations were those for
which smoking is a strong risk factor.[62] In the Linxian trial, conducted in
Linxian, China, where the prevalence of GI cancers is remarkably high,
there was a 9% reduction in cancer mortality, and a 21% reduction in
mortality from stomach cancer after 5 years of supplementation with -
carotene 14 mg, -tocopherol 20 mg, and selenium 50 mg.[63]

In the Chicago Western Electric Study,[64] dietary -carotene and vitamin C

were studied in relation to the risk of prostate cancer over a 30-year
follow-up period. Although no association with the risk of prostate cancer
was found, survival was greater in men with higher consumptions of -
carotene and vitamin C.

A study of women with cervical neoplasia or cancer evaluated the plasma

concentrations of -carotene, lycopene, canthaxanthin, retinol, -
tocopherol, and -tocopherol. Plasma concentrations of all the
antioxidants studied except -tocopherol were significantly reduced,
suggesting a role of antioxidant deficiency in women with cervical cancer.
[65]
Another study found a protective role for lycopene. In this study,
women with the greatest serum concentrations of lycopene had a
significantly reduced risk for developing cervical dysplasia.[66] The effects
of -carotene for treating certain precancerous lesions have been
investigated, as well. Supplemental -carotene may have a beneficial
effect for treating oral leukoplakia,[67] but does not appear to have any
benefit for treating patients with cervical dysplasia.[68,69]

Several studies have found a protective effect against breast cancer with
-carotene, whereas others have failed to find an association.[70-72] A diet
high in -carotene, vitamin E, and calcium has been found to be
protective against breast cancer.[73] Another study found that the dietary
antioxidants -cryptoxanthin, lycopene, lutein, and zeaxanthin protect
against breast cancer.[74] Other authors have concluded that the
consumption of fruits and vegetables high in carotenoids and vitamins A,
C, and E may reduce risk of breast cancer in premenopausal women.
Thus, while it appears that a diet high in fruits and vegetables is
associated with reduced breast cancer risk, the specific nutrients
associated with reduced risk remain uncertain.[70]

On the other hand, the Physicians' Health Study, a large and prominent
study, did not find a reduction of cancer risk from -carotene intake. This
study investigated the effect of supplemental -carotene 50 mg every
other day for 12 years in 22,000 male physicians. No change was found
in overall incidence of cancer or risk of death from cancer from taking
supplemental
-carotene.[75] Additional analysis associated supplemental -carotene
with a significant reduction in the risk of prostate cancer in men with low
baseline plasma concentrations of -carotene compared with those with
high baseline concentrations, who had a marginal increase in risk.[76]
Further study is needed to collaborate these findings.

Lycopene, along with other compounds in tomato products, has been

found to reduce the risk of cancer of the prostate, pancreas, and the GI
tract.[77,78] Vitamin E, selenium, and lycopene have promising roles in the
chemoprevention of prostate cancer.[79 Additional research is under way
to investigate the chemopreventive potential of green tea flavonoids,
lycopene, vitamin E, and selenium.[80,81]

Finally, a recent analysis of the Cancer Prevention Study II (CPS-II), a

prospective mortality study of more than 1 million adults in the United
States, investigated the effects of supplemental multivitamins and/or
vitamins A, C, and/or E on mortality during a 7-year follow-up period. In
this study, the use of a multivitamin plus vitamin A, C, and/or E
significantly reduced the risk of all cancers in former smokers and in
individuals who had never smoked.[82]

Prevention in Smokers Unfortunately, data investigating the effects of

antioxidant supplementation in individuals who smoke have not
demonstrated a reduction in cancer risk. In fact, it appears that
supplemental (but not dietary) antioxidants may actually increase the risk
of cancer in smokers (Table 5).

A large Finnish trial referred to as the ATBC trial studied the effects of
synthetic -carotene 20 mg/day with or without vitamin E over 5 to 8
years in 29,133 male smokers. Surprisingly, -carotene was associated
with an 18% increase in the incidence of lung cancer; however, no
interaction with vitamin E was noted.[83]

A second trial called the Carotene and Retinol Efficacy Trial (CARET)
studied the effect of synthetic -carotene 30 mg/day and vitamin A 25,000
IU in smokers, former smokers, and workers exposed to asbestos. In this
study, patients receiving antioxidant supplementation were found to be at
increased risk for lung cancer, CVD, and all-cause mortality. This
increased risk was of a lower magnitude in former smokers, and a greater
magnitude in heavy consumers of alcohol. After 4 years, the study was
stopped 21 months short of completion.[84,85]

In addition, the CPS II study found an increase in the risk of death due to
lung cancer, prostate cancer, and all cancers in male smokers who used
a multivitamin plus vitamin A, C, and/or E, compared with those who
reported no vitamin use. No association with smoking was seen in
women.[82]

One possible explanation for these surprising findings is that

-carotene is susceptible to oxidative damage from alcohol and the gases
in cigarette smoke, which may lead to the formation of harmful
byproducts.[86] Research indicates that there may be significant
differences between smokers and nonsmokers in the level of oxidative
DNA damage associated with supplemental -carotene, with decreases
in nonsmokers and increases in smokers. Thus, it appears that smoking
and alcohol may somehow alter -carotene, resulting in adverse effects.
Additional research suggests that vitamin C protects against the harmful
effects of -carotene in smokers, leading to the conclusion that smokers
should take vitamin C supplements in conjunction with -carotene
supplementation but should not take -carotene supplements alone.[87]

Another possible explanation is that isolating -carotene from the

combination of nutrients that occur in natural food sources and
administering it at doses greater than could normally be obtained from
the diet may have led to the detrimental effects seen in the ATBC and
CARET trials. -carotene may be dependent on other antioxidants, such
as vitamins C and E, to exert protective effects, or may only be beneficial
at dietary levels.[6,88] Finally, both the ATBC and CARET trials found that
higher blood concentrations of -carotene upon entry into the studies
(i.e., resulting from dietary consumption) were associated with a lower
risk of lung cancer, supporting the conclusion that dietary but not
supplemental -carotene may be beneficial in smokers.[87]

Additional evidence supporting the conclusion that the results from the
ATBC and CARET trials could be attributed to the use of supplemental -
carotene is provided by data showing that supplemental forms of -
carotene have markedly greater bioavailability than -carotene from
foods.[6,88] As shown in Table 6, the plasma concentrations that were
achieved in studies that found an increased risk of lung cancer were
much greater than those achieved with dietary intake. Thus, 20 mg/day of
supplemental -carotene may raise plasma concentrations to a range
associated with lung cancer, but 20 mg/day of dietary -carotene will not.
[6]

Secondary Prevention A handful of studies have shown beneficial

effects of antioxidant supplementation for preventing cancer recurrence.
Results from these trials have been mixed.

In one study, supplementation with -carotene 50 mg/day for 5 years had

no effect on the occurrence of new basal cell or squamous cell
carcinomas in patients who previously had skin cancer; however, the
follow-up period may not have been long enough to detect an effect.[89,90]
The Nutritional Prevention of Cancer Study Group investigated the effects
of selenium 200 mcg/day versus placebo for a mean of 4.5 years in
patients with a history of basal cell or squamous cell skin cancer. In this
study, selenium treatment did not significantly affect the incidence of skin
cancer recurrence. However, secondary analyses found that selenium did
significantly decrease total cancer mortality and the incidence of lung,
colorectal, and prostate cancer.[91]

In another study, -carotene 25 mg/day with or without vitamin C 1

gram/day and vitamin E 400 mg/day for 5 to 8 years was not found to
reduce the occurrence of colorectal adenomas in patients with a prior
history of adenomas.[92]

Finally, -carotene may play a protective role for women who already
have breast cancer. One study found that over a 6-year period, only 1
death occurred in the group with the highest
consumption of -carotene, compared with 8 and 12 deaths in the
intermediate and lowest groups of consumption, respectively.[93]

Treatment During treatment for cancer, one mode of action of certain

chemotherapeutic agents known as alkylating agents involves the
intentional generation of free radicals to cause cellular damage and
necrosis of malignant cells. Therefore, there has been concern that
antioxidant compounds taken during chemotherapy could reduce the
effects of chemotherapy on malignant cells.[94,95 However, much published
research actually indicates that antioxidants can be beneficial in the
treatment of cancer, either as sole agents or as adjuncts to standard
radiation and chemotherapy protocols.[94] Antioxidants have been found to
both prolong survival and to reduce some of the adverse events
associated with chemotherapy.[96,97] The doses of antioxidants required to
demonstrate clinical benefit in the treatment of cancer are greater than
those recommended for general population use.[41,94,98,99] Research
supporting the use of coenzyme Q10 for the treatment of breast cancer is
also promising.[100-102]

A detailed review of the use of antioxidant supplements in the treatment

of cancer by Lamson and Brignal[94] has concluded that antioxidants have
synergistic effects with a number of anticancer medications, with three
caveats: (1) The flavonoid tangeretin should not be used with tamoxifen
(some researchers suggest that all flavonoids should be avoided in
patients treated with tamoxifen until further research establishes their
safety); (2) N-acetylcysteine should not be used with doxorubicin; and (3)
-carotene should not be used with 5-fluorouracil.

Respiratory Disorders

Because of the widespread effects of oxidation in the body, it is possible

that antioxidants protect against a wide array of other ailments, such as
certain respiratory disorders. Asthma is characterized by chronic airway
inflammation. The generation of oxygen free radicals by activated
inflammatory cells produces many of the pathophysiologic changes
associated with asthma and may contribute to its pathogenesis.[103 ]
Therefore, antioxidant nutrients may play a role in the prevention and
treatment of asthma.
Vitamin C is the major antioxidant present in the surface of the lung,
suggesting a protective antioxidant role.[104] A number of studies support
the use of vitamin C in allergy and asthma; however, others have failed to
find a beneficial effect.[105] Consumption of fresh fruit rich in vitamin C
(citrus fruits and kiwifruit) has been found to have a beneficial effect --
wheezing, nocturnal cough, and chronic cough were significantly reduced
in children who consumed fresh fruit at least weekly.[106]

Vitamin C intake in the general population is inversely correlated with the

incidence of asthma, suggesting that a diet low in vitamin C is a risk
factor for asthma.[104] Symptoms of asthma in adults are decreased by
vitamin C supplementation.[104] Vitamin C 2 grams/day was found to be
protective against airway responsiveness to viral infections, allergens,
and irritants.[107] Evidence of an effect against symptoms in some patients
with exercise-induced asthma was found with 2 grams/day.[108] Another
study found decreased serum concentrations of -tocopherol, -carotene,
and vitamin C in children with asthma, even during asymptomatic
periods.[109] Although evidence is mounting that vitamin C intake may
prevent the development of asthma or certain symptoms of asthma,
vitamin C should not be relied upon for the treatment of asthma.[105,110] In
addition, dietary vitamin E may have a mild protective effect against the
development of asthma.[111]

There is much public interest in the use of vitamin C to protect against the
common cold. Although some studies have found a beneficial effect,
reviews generally conclude that doses of 500 to 1,000 mg/day of vitamin
C have no significant effect on overall incidence of the common cold, but
provide some benefits in terms of duration and severity. It is believed that
these improvements are due to the antihistaminic action of vitamin C in
very large doses, and not related to antioxidant effects.[6]

Cardiovascular Disease

Of all the chronic diseases in which excess oxidative stress has been
implicated, CVD has the strongest supporting evidence for the beneficial
role of antioxidants. Oxidation of LDL-C may be a key step in the
development of atherosclerosis, and atherosclerosis and hypertension
are known risk factors in the development of CVD.[6] Thus, antioxidants
are potentially useful in preventing or delaying the development of
atherosclerosis, and in preventing heart disease.[112]

Vitamin E is primarily carried in LDL-C and is particularly effective in

protecting it against oxidation.[113] In addition, vitamin E can inhibit smooth
muscle cell proliferation, an important component of atherogenesis.[114
Finally, vitamin E may reduce risk of CVD through its effect on platelet
function. Laboratory data, animal studies, and epidemiologic data also
support the hypothesis that vitamin E may reduce risk of CVD.[113] As an
antioxidant, -carotene has been shown to inhibit oxidative damage to
cholesterol and protect against atherosclerotic plaque formation.[37]

Vitamin C has been found to have antihypertensive properties. A British

study of people 65 years or older found that intake of vitamin C and
plasma concentrations of vitamin C were inversely correlated with systolic
and diastolic blood pressures and pulse rate.[115] Additional studies have
shown that vitamin C supplementation can reduce blood pressure.[17] The
other antioxidant vitamins have not been shown to have antihypertensive
effects.

Epidemiologic studies show that diets rich in fruits and vegetables,

vitamin C, vitamin E, and carotenoids are associated with a decreased
risk of heart disease.[6] However, prospective randomized trials
investigating the use of supplemental antioxidants have not been
consistent. Ongoing trials among high-risk, apparently healthy individuals
and among patients with CVD are expected to shed further light on this
issue.[6]

In women, it was found that the risk of nonfatal acute myocardial

infarction (MI) was inversely related to dietary intake of foods containing
-carotene, but not those containing retinol.[116] In addition, the EURAMIC
case-control study investigated blood concentrations of carotenoids in
people from 10 European countries. This study found that -carotene, -
carotene, and lycopene were all associated with reduced risk of MI; the
protective effects of lycopene were strongest.[117] However, most
observational studies have found no benefit in the reduction of CVD with
higher dietary or supplemental intake of vitamin C.[113]

In the Physicians' Health Study, physicians receiving -carotene 50 mg

on alternate days did not experience a change in risk of CVD during 12
years of follow-up. However, subgroup analysis suggested that -
carotene did decrease the risk for men who had a prior history of heart
disease.[75] Vitamin E, on the other hand, has been found to have a
protective effect against CVD at supplement levels of at least 100 IU per
day.[113]

The Chicago Western Electric Study found a modest decrease in the risk
of stroke in individuals with a higher intake of dietary -carotene and
vitamin C. However, the authors concluded that the data were not strong
enough to provide definitive evidence that high intake of antioxidant
vitamins decreases the risk of stroke.[118]

The analysis of CPS II (described earlier) also investigated the effects of

multivitamin and vitamin A, C, and/or E supplementation on the risk of
CVD. This study found that the risk of death due to ischemic heart
disease was significantly decreased in those who used multivitamins
alone, vitamins A, C, and/or E alone, or a multivitamin plus vitamin A, C,
and/or E, compared with those who used no supplemental vitamins. The
risk of death due to stroke was also reduced, but only in adults without a
prior history of CVD who took vitamins A, C, and/or E with or without a
multivitamin.[82]

Ocular Disorders

The eye is at particular risk of oxidative damage due to high oxygen

concentrations, large amounts of oxidizable fatty acids in the retina, and
exposure to ultraviolet rays. In Western countries, age-related macular
degeneration (AMD) is the leading cause of blindness among older
people.[119] Cataracts are also a widespread problem among the elderly.

The carotenoids lutein and zeaxanthin are believed to be particularly

important in preventing ocular damage, because they absorb blue light
and protect against short wavelength damage to the retina.[4]

Macular Degeneration Epidemiologic studies show that there is a

decreased incidence of AMD in smokers and nonsmokers with higher
intakes of fruits and vegetables, particularly those that have high levels of
lutein and zeaxanthin.

The French POLA study examined plasma concentrations of vitamin E

and the incidence of AMD in a population of elderly individuals. This
study found a significant inverse relationship between plasma
concentrations of vitamin E and AMD incidence. No association was
found with plasma concentrations of either vitamin C or vitamin A.[119
Similar observations have been made in the case of smokers, who are at
an increased risk for developing AMD.[6] However, no causal relationship
has been established.

Cataracts Animal experiments and epidemiologic studies indicate that a

large intake of antioxidant vitamins reduces the risk of cataract and
macular degeneration.[120,121] Several observational epidemiologic studies
have examined the relationship of cataracts and intakes of vitamin C,
vitamin E, and carotenoids. For example, one study found that low serum
concentrations of vitamin E and -carotene were found to be risk factors
for en -stage cataracts. No associations were found with serum
concentrations of selenium or retinol.[122] Another study found that dietary
intake of fruits and vegetables containing a variety of nutrients, including
vitamin C, vitamin E, and carotenoids, was inversely related to the risk of
cataracts.[19]
Because these studies are observational, they cannot prove that these
dietary components can actually prevent cataracts, and further study is
needed.[6] However, a recent prospective study of dietary intake found
that increased consumption of lutein and zeaxanthin reduces the risk of
developing cataracts severe enough to require extraction.[123]

Pharmaceutical Care and Antioxidant Supplements

Consumers are likely to be overwhelmed with the research on dietary
supplements reported by the lay press, and may have difficulty assessing
the many different messages from these studies. In addition, they may
need assistance interpreting the new DRIs. Therefore, they are likely to
turn to pharmacists for more information.

One of the first steps in counseling patients about the use of dietary
supplements is to assess their goals of therapy. Pharmacists can help to
shape patients' expectations of the benefits of supplements, and explain
that supplements are not a quick fix for health problems. In addition,
pharmacists should explain that the pathogenic processes that lead to the
development of disorders such as cancer and CVD take place over
decades, and that lifestyle choices over time affect long-term health.

When counseling patients on the use of dietary supplements, it is

important to emphasize that overall dietary and lifestyle factors, including
consumption of fruits and vegetables, regular exercise, cessation or
avoidance of smoking, and moderation in the use of alcohol, are all
important risk factors for disease. Although dietary supplements may play
a role in optimal health, they are not a substitute for other healthful habits.
Pharmacists should help guide patients towards healthful lifestyles and
recommend important dietary sources of various antioxidant nutrients as
well as antioxidant supplements.

Pharmacists should recommend that all individuals strive to achieve an

antioxidant intake that at least meets RDA levels. In addition, the
potential benefits of higher doses should be emphasized. For vitamin C,
supplements of 500 to 2,000 mg/day may be recommended for the
prevention of cancer and respiratory disorders, and the treatment of the
common cold. Vitamin C is best when taken in divided doses throughout
the day. Patients taking vitamin E should be advised that supplements of
at least 100 mg/day are necessary to achieve cardiovascular benefits.

Selenium is beneficial in doses up to 200 mcg/day to maximize

antioxidant potential. It is best to take antioxidants together. For example,
vitamin C renews the antioxidant capacity of vitamin E. Finally, synthetic
-carotene supplements should be avoided, particularly by smokers.
Patients should be advised to consume 5 to 6 servings of fruits and
vegetables daily to achieve recommended carotenoid intake.

Appropriate counseling regarding UL intakes should emphasize that

these are not target intakes for nutrients, and that there are no
established benefits of taking doses close to UL limits. Instead, these
limits should be used as a guide for patients.

Many consumers who purchase dietary supplements may also be

pharmacy patients. Pharmacists should review prescription and over-the-
counter medications that patients are taking and be vigilant for possible
interactions with dietary supplements. In addition, pharmacists who note
that a patient is receiving pharmacotherapy for certain conditions, such
as hypertension or dyslipidemias, may wish to educate the patient about
the known benefits of antioxidant nutrients for those conditions.

Conclusion
Free radicals cause oxidative damage to cells and DNA, which can be
reduced by antioxidants. Antioxidant nutrients appear to play an
important role in protection against various disorders. However, isolation
of specific antioxidant nutrients may not confer the same health benefits
as do whole foods. For smokers, the use of -carotene may be
detrimental, particularly if it is administered in isolation.

Observational studies provide fairly consistent data for an inverse

association between high intake of antioxidant vitamins and cancer risk.
Data are strongest for -carotene and vitamin C. However, trials
investigating the benefits of antioxidant supplements as either primary or
secondary prevention have not necessarily supported these findings.
There are a number of possible explanations for these inconsistencies:
results from observational studies are complicated by other behavioral
factors; the protective role of the combinations of nutrients in fruits and
vegetables is responsible for reduction in risk and treatment, whereas a
single component is ineffective; and the follow-up period is inadequate in
most randomized trials.[124]

For cardiovascular risk, -carotene and vitamin E appear to modify the

oxidation of LDL-C, making it less atherogenic, and vitamin C appears to
reduce hypertension. These effects combine to reduce risk of CVD.
Interventional studies have not provided conclusive data about the
benefits of supplemental interventions, but it appears that -carotene
from fruits and vegetables and supplemental vitamin E are beneficial in
the prevention of CVD, whereas synthetic -carotene should be avoided.
The carotenoids, vitamin E, and vitamin C are implicated in the
maintenance of ocular function, and vitamins C and E appear to offer
some protection against asthma.

In general, however, the greatest benefits of antioxidant nutrients are

seen in epidemiologic surveys in which antioxidant nutrients are primarily
derived from dietary sources, particularly fruits and vegetables. It is not
known whether these benefits can be specifically attributed to the
antioxidant nutrients identified in these foods. Therefore, current
recommendations stress the importance of maintaining a varied diet that
is high in fruits and vegetables. Further research is needed to clarify the
benefits provided by antioxidant supplements.

Acknowledgements
The author wishes to thank Judy Crespi-Lofton, MS, for her technical
assistance with the manuscript.
Funding Information
The author declares no conflicts of interest or financial interests in any
product or service mentioned in this article, including grants, employment,
stock holdings, gifts, or honoraria.