Dr. James Manos (MD)
October 16, 2020
Antioxidants
Dietary supplement description
Antioxidants
are molecules that can inhibit the oxidation of other
molecules. Oxidation is a chemical
reaction that transfers electrons from a substance to an oxidizing agent.
Oxidation reactions can produce free radicals. These free radicals can start
chain reactions that damage cells. Antioxidants terminate these chain reactions
by removing free radical intermediates and inhibiting other oxidation reactions. They do this by being
oxidized themselves, so antioxidants often reduce agents such as thiols, ascorbic acid (a form
of vitamin C), or polyphenols (11).
Anthocyanosides, plant pigments, have excellent antioxidant
properties. They scavenge damaging
particles in the body known as free
radicals, helping prevent or reverse damage to cells (13).
Oxidative
stress may contribute to the development of many diseases, including
cardiovascular disease, diabetes, rheumatoid arthritis (RA), and
neurogenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease
(PD), and motor neuron diseases. In many
diseases, it is unclear if oxidants trigger the disease or if they are produced
as a secondary consequence of the disease and from general tissue damage. Oxidative damage in DNA can also cause cancer. Also,
LDL (low-density lipoprotein) oxidation appears to trigger the process of
atherogenesis (a condition in which an artery wall
thickens because of the accumulation of fatty materials such as
cholesterol), which results in atherosclerosis (hardening of the arteries) and finally cardiovascular disease (11).
Antioxidants are substances that may
protect cells against the effects of free radicals. Free radicals are molecules produced when the body breaks down food or
by environmental exposures like tobacco smoke and radiation. Free radicals can damage cells and may play a role in
heart disease, cancer, and other diseases. Antioxidant substances include beta–carotene, lutein, lycopene, selenium, and vitamins A, C, and E. Antioxidants are found in many foods. These include fruits, vegetables, nuts, grains, meats,
poultry, and fish (14).
Several
antioxidant enzymes, such as superoxide dismutase (SOD), catalase,
glutathione peroxidase, glutathione reductase, glutathione S-transferase, and others, protect DNA
from oxidative stress. It has
been proposed that polymorphisms in these enzymes are associated with DNA
damage and the individual’s risk of cancer susceptibility (11).
There are several antioxidants that may
help in preventing cancer, aging, and many diseases. Very good antioxidants are resveratrol (a kind of plant
hormone, flavonoids, polyphenols, anthocyanidins, anthocyanins, tannins, catechins, proanthocyanidins and terpenoids (plant
antioxidants;). A great proportion of antioxidants are contained in red wine. However, consuming too much wine is harmful.
Oxygen Radical
Absorbance Capacity (ORAC) measures antioxidant capacities in biological samples in vitro. A wide variety of foods have been tested using this methodology, with certain spices, berries, and legumes
rated highly in extensive tables once published by the USA Department of Agriculture (USDA). Still, these were withdrawn in 2012 as biologically invalid,
as no physiological proof in vivo
exists that the free–radical theory is valid. Consequently, the ORAC method, derived only from in vitro experiments, cannot be
interpreted as relevant to human diets or biology (8).
There are several assay methods
to measure the antioxidant capacities of foods. These methods are based on
different underlying mechanisms and use different radical and oxidant sources.
Therefore, any single method does not measure ΄΄total antioxidant activity΄΄. This would require an array of assays to get the full
profile of antioxidant activity (Ou et al 2002). This point is illustrated by
comparing the same samples analyzed by different assays. The FRAP assay measures ferric
ion-reducing activity, while the ORAC assay estimates peroxy radical scavenging
activity. The ranking of foods analyzed by the two
methods differs, particularly when presented per typical serving size. When similar foods are analyzed
by the same method, the variation could be attributed to the application of the
method by different laboratories, using different samples, different
cultivars, seasons, harvesting times, etc. (6).
Uses in medicine
Antioxidants have been shown to help
prevent a number of long-term illnesses, such as heart disease, cancer, and an
eye disorder called macular degeneration. Animal studies have found that anthocyanosides may strengthen blood vessels, improve
circulation, and prevent the oxidation of LDL cholesterol (΄΄bad΄΄ cholesterol), a major risk factor for atherosclerosis (hardening of the arteries). Research on humans is
needed (13).
Published studies (abstracts)
Antioxidant properties
A study analyzed a variety of foods, including 34
vegetables, 30 fruits, 34 beverages, and 6 vegetable oils, using three different assays, i.e. Trolox equivalent
antioxidant capacity (TEAC),
total radical-trapping antioxidant parameter (TRAP), and ferric reducing-antioxidant power (FRAP). These assays, based on
different chemical mechanisms, were selected to take into account the wide variety and range of
action of antioxidant compounds present in actual foods. Among vegetables,
spinach had the highest antioxidant capacity in the TEAC and FRAP assays, followed by peppers, whereas asparagus had the greatest
antioxidant capacity in the TRAP assay. Among fruits, the highest antioxidant activities were found in berries (i.e., blackberry,
redcurrant, and raspberry). Among beverages,
coffee had the greatest TEAC, followed by citrus juices, which exhibited the
highest value among soft beverages. Finally, soybean oil had the highest antioxidant capacity, followed by extra virgin olive oil, whereas peanut
oil was less effective (5).
A study investigated the antioxidant
activities of 22 common vegetables, one green tea, and one black tea measured
using the automated oxygen radical absorbance
capacity (ORAC) assay. Based on
the fresh weight of the vegetable, garlic had the highest antioxidant activity (μmol of Trolox equiv/g) against
peroxyl radicals (19.4) followed by kale (17.7), spinach (12.6), Brussels sprouts, alfalfa
sprouts, broccoli flowers, beets, red bell pepper, onion, corn, eggplant
(9.8 – 3.9), cauliflower,
potato, sweet potato, cabbage, leaf lettuce, string bean, carrot, yellow
squash, iceberg lettuce, celery, and cucumber (3.8 – 0.5). Kale had the highest antioxidant
activity against hydroxyl radicals, followed by Brussels sprouts, alfalfa sprouts,
beets, spinach, broccoli flowers, and others. The green and black teas had much
higher antioxidant activities against peroxyl radicals than all these vegetables. However, the tea also showed prooxidant activity in the presence of Cu2+, which was not
found in any of the vegetables studied
(3).
Another study investigated the total antioxidant activity of 12 fruits and 5 commercial fruit juices using an automated oxygen radical absorbance capacity (ORAC) assay. On the basis of the wet weight of the fruits (edible portion), strawberry had the highest ORAC activity (micromoles of Trolox equivalents per gram) followed by plum, orange, red grape, kiwi fruit, pink grapefruit, white grape, banana, apple, tomato, pear, and honeydew melon. Based on the dry weight of the fruits, strawberry again had the highest ORAC activity, followed by plum, orange, pink grapefruit, tomato, kiwi fruit, red grape, white grape, apple, honeydew melon, pear, and banana. Most of the antioxidant capacity of these fruits was from the juice fractions. The contribution of the fruit pulp fraction (extracted with acetone) to the total ORAC activity of fruit was usually less than 10%. Among the commercial fruit juices, grape juice had the highest ORAC activity, followed by grapefruit, tomato, orange, and apple juice (2).
A study on anthocyanins concluded that different berries contain unique patterns of
anthocyanins. These berries are good resources for the novel genes
involved in anthocyanin production. There are already a number of reports on
the antioxidant activity of berry extracts by several methods, such as oxygen
radical absorbance capacity (ORAC) or
DPPH radical scavenging capacity, indicating that bilberry and black currant possess almost equal
antiradical activities. Chokeberries were also shown to possess strong antioxidant activity. Moreover, delphinidin 3-glucoside (found abundantly in bilberry and black currant), delphinidin 3-rutinoside (found only in black currant), and cyanidin
3-glucoside (found abundantly in bilberry
and elderberry) were
reported to have relatively strong
antiradical activity among various anthocyani(di)ns. From these reports, bilberry, black currant, and chokeberry extracts can be regarded as health-beneficial functional foods from the view of the radical
scavenging activity (1).
In a study, different cultivars of four Vaccinium species were analyzed for total phenolics, anthocyanins, and antioxidant capacity (oxygen radical absorbance capacity, ORAC). The total antioxidant capacity of different berries studied varied in distinct species and cultivars of Vaccinium. Increased maturity at harvest increased the ORAC, the anthocyanin, and the total phenolic content. The growing location did not affect ORAC, anthocyanin, or total phenolic content. A linear relationship existed between ORAC and anthocyanin or total phenolic content. Blueberries are one of the richest sources of antioxidant phytonutrients of the fresh fruits and vegetables studied (4).
Fruits and leaves from different cultivars
of thornless blackberry
(Rubus sp.), red
raspberry (Rubus idaeus L.), black raspberry (Rubus occidentalis L.), and strawberry (Fragaria x ananassa D.) plants were
analyzed for total antioxidant capacity (oxygen
radical absorbance capacity, ORAC) and total phenolic content. Also,
fruits were analyzed for total anthocyanin content. The results showed that blackberries and strawberries had the highest ORAC values during the green stages,
whereas red raspberries had the highest ORAC activity at the ripe stage.
Total anthocyanin content increased with maturity for all three species of
fruits. Compared with fruits, leaves were found to
have higher ORAC values. As the leaves become older, the ORAC values and total
phenolic contents decrease. The results showed a
linear correlation between total phenolic content and ORAC activity for fruits
and leaves. A linear relationship existed for ripe berries between ORAC values
and anthocyanin content. Of the ripe fruits tested, based on the wet weight
of the fruit, cv. Jewel black raspberry and
blackberries may be the richest source of
antioxidants. Regarding the dry weight of the fruit, strawberries had the
highest ORAC activity, followed by black raspberries (cv. Jewel), blackberries,
and red raspberries (12).
Beneficial role on multiple sclerosis
(MS)
A
review concluded that based on available evidence, the prophylactic use of vitamin D
is a viable option as an adjunct to conventional medicine. Although there is a lack of conclusive evidence to
support the use of other non-conventional treatments, patients are still opting
to trial and bear the risks of these products, which are accessible without the
intervention of a healthcare professional. Controlled, evidence-based trials
are essential for healthcare professionals to competently intervene and recommend
these products (34).
Safety – side effects
Dietary flavonoids ingested by the pregnant mother related to
infant leukemia
There is also a concern that dietary flavonoids pregnant women take may cause later in the infant leukemia in the first year of life. In utero (in the womb), there may be a critical interval when exposure to high
levels of flavonoids and increased hematopoietic cell proliferation can lead to
recombination involving MLL. The question is if flavonoids cross the placental barrier in humans. In
studies in which a radioactive synthetic flavonoid was injected into pregnant
rats, all fetal tissues investigated demonstrated the presence of the
flavonoid, suggesting that it crossed the placental barrier. However, further studies are needed to determine whether ingestion
of common dietary flavonoids by humans results in a similar phenomenon and
answer the question of increased maternal consumption during pregnancy of foods
that contain dietary topoisomerase II inhibitors is positively associated with
infant leukemia (10).
Relation to cancer development
No dietary factor or ingested
substance has been implicated in the etiology of esophageal carcinoma, especially in high-risk areas of the world. Although not well defined, there is heavy consumption
of tannin-rich foods, particularly
sorghum, by populations at high risk for
carcinoma. The carcinogenic properties of tannins and extracts of tannin-rich
plants have been demonstrated experimentally. It is proposed herein that salivary
proline-rich proteins (PRPs), by binding ingested tannins, protect the esophagus
from the carcinogenic effects of the latter. It is also possible that genetic
variants of PRPs may influence the incidence of esophageal cancer in different
populations (9).
Increased mortality
A Cochrane systematic review included 78 randomized clinical trials. In total, 296,707 participants were
randomized to antioxidant supplements (beta-carotene,
vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no
intervention. A total of 21 484 of 183 749 participants
(11.7%) were randomized to antioxidant supplements, and 11 479 of 112 958
participants (10.2%) randomized to placebo or no intervention died. The review showed an increased risk of mortality associated with beta-carotene and possibly
vitamin E and vitamin A but was not associated with vitamin C or selenium use. The review concluded that the current evidence does not
support using antioxidant supplements in the general population or patients with various diseases (21).
Antioxidant supplements are used for the prevention of several diseases. A
review assessed the effect of antioxidant supplements on
mortality in randomized primary and secondary prevention trials. The authors
included 68 randomized trials with 232 606 participants (385 publications). The
review concluded that the treatment of beta carotene, vitamin A, and vitamin E may
increase mortality. Vitamin C and selenium's potential role in mortality
need further study (16).
Another review assessed the effect of
antioxidant supplements on mortality in primary or secondary prevention
randomized clinical trials. Sixty-seven randomized trials with 232 550 participants
were included. The authors found no
evidence to support antioxidant supplements for primary or secondary
prevention. Vitamin A, beta-carotene, and vitamin E may
increase mortality. Future randomized
trials could evaluate the potential effects of vitamin C and selenium for
primary and secondary prevention. Such trials should be closely monitored for
potential harmful effects. Antioxidant
supplements must be considered medicinal products and undergo
sufficient evaluation before marketing (17).
Antioxidant use during cancer therapy
(including chemotherapy & radiotherapy)
The use of antioxidants during cancer
therapy is currently a topic of heated debate because of an overall lack of
clear research findings. Some data suggest antioxidants can ameliorate toxic
side effects of therapy without affecting treatment efficacy, whereas other
data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to
potential interactions between ROS and dietary antioxidants and their effects on
human health indicates that consuming dietary antioxidant supplements has pros
and cons for any population and raises numerous questions, issues, and
challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to
generalize and make specific recommendations about antioxidant usage for those
at high risk for cancer or undergoing treatment (18).
Despite nearly two decades of research
investigating the use of dietary antioxidant supplementation during
conventional chemotherapy and radiation therapy, controversy remains about the
efficacy and safety of this complementary treatment. Several randomized clinical trials have demonstrated that concurrently administering antioxidants with chemotherapy or radiation
therapy reduces treatment-related side effects. Some data indicate that antioxidants may protect tumors and healthy cells from oxidative damage generated by radiation therapy and chemotherapeutic agents. However, other data suggest that antioxidants can protect normal
tissues from chemotherapy- or radiation-induced damage without decreasing tumor
control. A review concluded that the use of supplemental antioxidants during
chemotherapy and radiation therapy should be discouraged because of the
possibility of tumor protection and reduced survival (19).
Beta carotene
(see also above ΄΄Increased mortality΄΄)
Beta-carotene is likely safe when used for certain specific medical conditions and
taken in appropriate amounts. However, beta-carotene supplements are not recommended
for general use. Beta-carotene
is possibly unsafe in high doses,
especially when taken long-term (23). Beta-carotene
supplements may increase the risk of heart disease and cancer in those who
smoke or drink heavily. Heavy smokers or drinkers should not use this supplement except under a doctor's supervision (22). There is growing
concern that taking high doses of antioxidant supplements such as beta-carotene
might do more harm than good. Some research
shows that taking high doses of beta-carotene supplements might increase the
chance of death from all causes and possibly other serious side effects. There is also concern that taking large
amounts of a multivitamin plus a separate beta-carotene supplement increases
the chance of developing advanced prostate cancer in men. Beta-carotene supplements might increase the risk of lung and prostate cancer in people who smoke. People who smoke should not take
beta-carotene supplements. In
people who have been exposed to asbestos, beta-carotene supplements might
increase the risk of cancer. People who
have been exposed to asbestos should not take beta-carotene supplements. There
is also some concern that when antioxidant vitamins, including beta-carotene,
are used together, they might have harmful effects after angioplasty. They can interfere with healing. Without a doctor's recommendation, people should not use beta-carotene and other antioxidant vitamins before or after angioplasty (23).
The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the
combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A)
taken daily against placebo in 18 314 men and women at high risk of developing
lung cancer. The CARET intervention was stopped 21
months early because of clear evidence of no benefit and substantial evidence
of possible harm; there were 28% more lung cancers and 17% more deaths in the
active intervention group (active =
the daily combination of 30 mg β-carotene
and 25 000 IU retinyl palmitate). Promptly after January 18, 1996, the announcement that the CARET active intervention had been stopped, the authors
published preliminary findings from CARET regarding cancer, heart disease, and
total mortality. The study concluded that CARET participants receiving the
combination of beta-carotene and vitamin A had no chemopreventive benefit and
had excess lung cancer incidence and mortality. The results are highly consistent with those found
for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study
in 29 133 male smokers in Finland. Individuals at high risk of developing lung cancer,
i.e., current smokers and asbestos-exposed workers, should be discouraged from
taking supplemental beta-carotene (and the combination of β-carotene with vitamin A). Safety and
efficacy should be demonstrated before recommending the use of vitamin supplements
in any population (15).
Vitamin C (L- ascorbic acid)
Vitamin C has low toxicity and is not
believed to cause serious adverse effects at high intakes. The most
common complaints are diarrhea, nausea, abdominal cramps, and other
gastrointestinal disturbances due to the osmotic effect of unabsorbed vitamin C
in the gastrointestinal tract. In postmenopausal (after menopause) women
with diabetes who participated in the Iowa Women’s Health Study, supplemental
(but not dietary) vitamin C intake (at least 300 mg/day) was significantly
associated with an increased risk of cardiovascular disease mortality. This finding is from a subgroup of patients in an
epidemiological study. No such
association has been observed in any other epidemiological study, so the
significance of this finding is uncertain. High vitamin C intake also has the
potential to increase urinary oxalate and uric acid excretion, which could
contribute to the formation of kidney stones, especially in individuals with
renal disorders. However, studies
evaluating the effects on urinary oxalate excretion of vitamin C intakes
ranging from 30 mg to 10 g/day have had conflicting results, so it is unclear whether vitamin C plays a role
in developing kidney stones. The best evidence that vitamin C
contributes to kidney stone formation is in patients with pre-existing
hyperoxaluria. Also,
in individuals with hereditary hemochromatosis, chronic consumption of high
doses of vitamin C could exacerbate iron overload and result in tissue damage. Under
certain conditions, vitamin C can act as a pro-oxidant, potentially
contributing to oxidative damage. A few studies in vitro have suggested that by acting as a pro-oxidant, supplemental oral vitamin
C could cause chromosomal and/or DNA damage and possibly contribute to cancer development.
However, other studies have not shown increased oxidative damage or cancer risk with high intakes of vitamin C. Other reported effects of high intakes of vitamin C
include reduced vitamin B12 and copper levels, accelerated metabolism or
excretion of ascorbic acid, erosion of dental enamel, and allergic responses. However, at least some of these conclusions were a
consequence of assay artifacts, and additional
studies have not confirmed these observations. Long-term intakes of vitamin C above the
tolerable upper intake levels (UL) may increase the risk of adverse health
effects (24).
Currently, the recommended upper limit
for ascorbic acid (AA) (vitamin C) intake is 2 000 mg/day. However, because AA
is endogenously converted to oxalate and appears to increase the absorption of
dietary oxalate, supplementation may increase the risk of kidney stones. The effect of
AA supplementation on urinary oxalate was
studied in a randomized, crossover, controlled design in which subjects
consumed a controlled diet in a university metabolic unit. The study showed that 1 000 mg ascorbic acid (AA) (vitamin C) twice each
day increased urinary oxalate and Tiselius Risk Index (TRI) for calcium oxalate
kidney stones in 40% of participants, both stone formers and non-stone formers (25).
Vitamin C is a potent antioxidant but can also be a pro-oxidant and glycated protein under certain
circumstances in vitro. These
observations led the authors to hypothesize that a high intake of vitamin C in
diabetic persons might promote atherosclerosis. A human study examined the relationship
between vitamin C intake and mortality from cardiovascular disease. The study concluded that when
dietary and supplemental vitamin C were analyzed separately, only supplemental
vitamin C showed a positive association with mortality endpoints. Vitamin C intake was unrelated to mortality from
cardiovascular disease in the non-diabetic subjects at baseline. In conclusion, a high vitamin C intake from supplements is
associated with an increased risk of cardiovascular disease mortality in
post-menopausal (after menopause) women with diabetes (26).
Vitamin E (alpha-tocopherol)
(see also above ΄΄Increased mortality΄΄)
Research has not found any adverse
effects from consuming vitamin E in food; however, high doses of
alpha-tocopherol supplements can cause hemorrhage and interrupt blood
coagulation in animals, and in vitro data suggest that high doses
inhibit platelet aggregation. Two
clinical trials have found an increased risk of hemorrhagic stroke in
participants taking alpha-tocopherol; one trial included Finnish male smokers
who consumed 50 mg/day for an average of 6 years, and the other trial involved a
large group of male physicians in the United States who consumed 400 IU every
other day for 8 years. Because most physicians in the latter study also took aspirin, this finding could indicate that vitamin E tends to cause bleeding. The FNB has
established ULs for vitamin E based on potential hemorrhagic effects.
The ULs apply to all forms of supplemental alpha-tocopherol, including the eight
stereoisomers present in synthetic vitamin E. Doses of up to 1 000 mg/day (1 500 IU/day of the natural form or 1 100 IU/day of the synthetic
form) in adults appear to be safe. However, the
data are limited and based on small groups taking at least 2,000 IU
for a few weeks or months. Long-term intakes above the UL increase the risk of
adverse health effects. Vitamin E
ULs for infants have not been established. Two
meta-analyses of randomized trials
have also raised questions about the safety of large doses of vitamin E,
including doses lower than the UL. These meta-analyses linked
supplementation to small but statistically significant increases in all-cause
mortality. One
analysis found an increased risk of death at 400 IU/day doses, although the risk began to increase at 150
IU. In the other analysis of studies of antioxidant supplements for disease
prevention, the highest quality trials revealed that vitamin E, administered
singly (dose range 10 IU–5 000 IU/day; mean 569 IU) or combined with up to four
other antioxidants, significantly increased mortality risk. The implications of
these analyses for the potential adverse effects of high-dose vitamin E
supplements are unclear. Participants in the studies included in these analyses
were typically middle-aged or older and had chronic diseases or related risk
factors. These participants often consumed other supplements in addition to
vitamin E. A review of the subset of studies in
which vitamin E supplements were given to healthy individuals for the primary
prevention of chronic disease found no convincing evidence that the supplements
increased mortality. However, results from the recently published, large
SELECT trial show that vitamin E supplements (400 IU/day) may harm adult men in
the general population by increasing their risk of prostate cancer (27).
A randomized, double-blind,
placebo-controlled primary-prevention trial was conducted to determine
whether daily supplementation with alpha-tocopherol (vitamin E), beta-carotene, or both would
reduce the incidence of lung cancer and other cancers. A total of 29 133 male
smokers 50 to 69 years of age from southwestern Finland were randomly assigned
to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene
(20 mg per day) alone, both alpha-tocopherol and beta carotene or placebo.
Follow-up continued for five to eight years. Among the 876 new cases of lung
cancer diagnosed during the trial, no reduction in incidence was observed among
the men who received alpha-tocopherol. Unexpectedly, the
authors observed a higher incidence of lung cancer among the men who received
beta carotene than those who did not. The authors found no evidence of an
interaction between alpha-tocopherol and beta-carotene with respect to the incidence
of lung cancer. Fewer cases of prostate cancer were diagnosed among
those who received alpha-tocopherol than those who did not. Beta carotene
had little or no effect on cancer incidence other than lung cancer. Alpha-tocopherol had no apparent effect on total
mortality, although more deaths from hemorrhagic stroke were observed among the
men who received this supplement than among those who did not. Total
mortality was 8 percent higher among the participants who received beta
carotene than among those who did not, primarily because there were more deaths
from lung cancer and ischemic heart disease. In conclusion, the
authors found no reduction in the incidence of lung cancer among male smokers
after five to eight years of dietary supplementation with alpha-tocopherol or
beta-carotene. In fact, this trial raises the possibility that these
supplements may have harmful and beneficial effects (28).
A population-based, randomized,
double-blind, placebo-controlled, 2 x 2 factorial design trial (the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study) determined if vitamin E
(dl-alpha-tocopherol) and beta carotene supplementations could be used in the prevention of stroke in men at elevated risk for
hemorrhagic or ischemic events. The study used alpha-tocopherol (vitamin E), 50 mg; beta carotene, 20 mg; both; or placebo. The study showed that vitamin E supplementation increased the risk of
subarachnoid hemorrhage and
decreased the risk of cerebral infarction in
hypertensive men but had no effect among normotensive men. Furthermore, it
decreased the risk of cerebral infarction, without elevating the risk of
subarachnoid hemorrhage, among hypertensive men with concurrent diabetes. Beta carotene supplementation appeared to
increase the risk of intracerebral hemorrhage and modestly decrease the risk of
cerebral infarction among men with
greater alcohol consumption. In
conclusion, vitamin E supplementation may prevent
ischemic stroke in high-risk hypertensive patients, but further studies are
needed (29).
Vitamin E can inhibit platelet
aggregation and antagonize vitamin K-dependent clotting factors. As a result, taking large doses with anticoagulant or antiplatelet
medications, such as warfarin (Coumadin
(R)), can increase the risk of bleeding,
especially in conjunction with low vitamin K intake. The amounts of supplemental vitamin E needed to produce clinically significant effects are
unknown but probably
exceed 400 IU/day (27).
A systematic review and meta-analysis of randomized, placebo-controlled trials evaluated
the effect of vitamin E supplementation on incident total, ischemic, and
hemorrhagic stroke. The meta-analysis concluded that vitamin
E increased the risk of hemorrhagic stroke by 22%
and reduced the risk of ischemic stroke by 10%. This differential risk pattern is obscured
when looking at a total stroke. Given
the relatively small risk reduction of ischemic stroke and the generally more severe outcome of hemorrhagic
stroke, widespread indiscriminate use of vitamin E should be cautioned against (30).
Experimental models and observational
studies suggest vitamin E supplementation may prevent cardiovascular
disease and cancer. However, several high-dosage vitamin E supplementation trials showed non-statistically significant increases in
total mortality. A meta-analysis of the dose-response relationship between vitamin E
supplementation and total mortality by using data from randomized, controlled
trials were conducted. The metanalysis concluded that high-dosage (equal to or more than 400 IU/day) vitamin E
supplements may increase all-cause mortality and should be avoided (20).
Zinc
Zinc can be harmful at a dose of 80 mg,
so people should be sure to take this combination only under their doctor’s
supervision. Zinc
can cause copper deficiency, so a small amount of copper is added to the
nutrients. In
the AREDS study, 7.5% of people who took zinc had problems, including urinary
tract infections, enlarged prostate, and kidney stones, compared to 5% of those who did not receive zinc (32).
Zinc toxicity can occur in both acute
and chronic forms. Acute adverse effects of high zinc intake include nausea,
vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches. One case
report cited severe nausea and vomiting within 30 minutes of ingesting 4 g of
zinc gluconate (570 mg elemental zinc). Intakes of 150–450 mg of zinc daily have been associated with chronic effects such as low copper status, altered
iron function, reduced immune function, and reduced levels of high-density
lipoproteins. Reductions in a copper-containing enzyme, a marker of
copper status, have been reported with even moderately high zinc intakes of
approximately 60 mg/day for up to 10 weeks. The doses of zinc used in the AREDS study (80 mg per
day of zinc in the form of zinc oxide for 6.3 years, on average) have been
associated with a significant increase in hospitalizations for genitourinary
causes, raising the possibility that chronically high intakes of zinc adversely
affect some aspects of urinary physiology. Long-term intakes of Zinc above the tolerable upper
intake levels (ULs) increase the risk of adverse health effects (31).
Zinc is a common dietary supplement widely believed to have beneficial health effects. To assess the impact of
high-dose supplemental zinc on genitourinary diseases, the authors analyzed a
recent randomized trial comparing zinc, antioxidants, and their combination with placebo for complications related to the genitourinary tract. In a further analysis of the recent Age-related Eye
Disease Study (AREDS), the authors examined the data pool for the primary
International Classification of Diseases, 9th revision codes given for hospital
admissions related to urological problems. The authors found a significant increase
in hospital admissions due to genitourinary causes in patients on zinc vs.
non-zinc formulations (11.1% vs. 7.6%). The risk was greatest in male patients. In the study group of 343 patients requiring hospital
admission, the most common primary International Classification of Diseases, 9th
revision codes included benign prostatic hyperplasia/urinary retention (benign
prostatic hyperplasia), urinary tract infection, urinary lithiasis, and renal
failure. When comparing zinc to placebo,
significant increases in urinary tract infections (UTIs) were found, especially in females (2.3% vs. 0.4%). Admissions for
urinary lithiasis approached significance in men on zinc compared to placebo
(2.0% vs. 0.5%). There was no increase
in the prostate or other cancers with zinc supplementation. A significant decrease in prostate cancer diagnoses
was seen in patients receiving antioxidants vs. a placebo. Subgroup analysis revealed that this
finding was significant in men who smoked but not in nonsmokers. The study concluded that zinc supplementation at elevated levels results in
increased hospitalizations for urinary complications compared to a placebo. These
data support the hypothesis that high-dose zinc supplementation has a negative
effect on select aspects of urinary physiology (33).
Available forms
Antioxidant substances include beta–carotene, lutein, lycopene, selenium, and vitamins
A, C, and E. Antioxidants are found in many foods.
These include fruits, vegetables, nuts, grains, meats, poultry, and fish (14).
There are several antioxidants that may
help in preventing cancer, aging, and many diseases. Good antioxidants are resveratrol (a plant
hormone), flavonoids, polyphenols, anthocyanidins, anthocyanins, tannins, catechins, proanthocyanidins, and terpenoids (plant
antioxidants). A great proportion of antioxidants are contained in red wine. However, consuming too much wine is harmful.
Many antioxidants are also contained in coffee (green coffee is said to be a good
antioxidant), black
chocolate, green tea, olive oil (it also has vitamin E), blackberry, blueberry, and cranberry (these
also help patients with urinary tract infections UTIs), cherry, palms, cabbage, broccoli,
acai palm, concord grapes, pomegranate, red wine, black cherry, etc. Also, many antioxidants are found in beetroots, garlic, cauliflower, melted tomato (which contains lycopene), and onion. Excellent antioxidants are also grapes. Lycopene
and sulforaphane are analyzed separately. See also selenium and beta–carotene.
Scientists haven’t concluded which
nutrients have the highest antioxidant activity. However, the candidates include
strawberry,
garlic, Brussels
sprouts, pomegranate, Kale, green & black tea, concord grape, red wine,
blueberry, black cherry, acai palm (acai berry), blackberry, raspberry, red
currant, spinach, asparagus, coffee,
citrus juices, soybean oil, extra virgin olive oil, red kidney beans,
cranberry, bilberry, black currant, and chokeberry.
Acai palm (berry) seems to have a high content of anthocyanidins (7).
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