review article Antioxidants – A Pharmacological Overview
Tharanya
Selvaraj, Ghadevaru Sarathchandra*
Department
of Pharmacovigilance Laboratory for Animal Feed and Food safety Centre for
Animal Health Studies, Tamil Nadu Veterinary and Animal Sciences University, India
Citation: Selvaraj T, Sarathchandra G (2018) Antioxidants - A Pharmacological Overview. Adv Anal Pharm Chem: AAPC-102. DOI: 10.29011/AAPC-102. 100002
1. Abstract
It is ironic that oxygen, an element indispensable for life, under certain situations has deleterious effects on the human body. Most of the potentially harmful effects of oxygen are due to the formation and activity of many chemical compounds, known as ROS, which have a tendency to donate oxygen to other substances. Free radicals and antioxidants have become commonly used terms in modern discussions of disease mechanisms [1]. In this modern world, due to the rapid advancement of civilization, industrialization, and overpopulation, scientific knowledge on antioxidants is important since most of the diseases are mediated through Reactive Oxygen Species (ROS).
3.
Introduction
Antioxidants have gained so much popularity mainly because they
are known to be involved with so many biological processes such as tissue
protection, immunity, health, maintaining homeostasis, aging, growth and
development. Antioxidant has been defined as any substance that delays,
prevents or removes oxidative damage to a target molecule [2,3] defined
antioxidants as “any substance that directly scavenges ROS or indirectly acts
to up-regulate antioxidant defenses or inhibit ROS production”. In other words,
we can define antioxidants as any molecule that inhibits the oxidation of
another molecule. A chemical reaction involving the loss of electrons and
increase in the oxidative state is termed as “oxidation.” Oxidation results in
the formation of free radicals that are unstable atoms and molecules deficit in
electrons. In the late 19th and early 20th century, extensive study was devoted
to the uses of antioxidants in important industrial processes, such as the
prevention of metal corrosion, the vulcanization of rubber, and the
polymerization of fuels in the fouling of internal combustion engines [4]. Early
research on the role of antioxidants in biology focused on their use in
preventing the oxidation of unsaturated fats, which is the cause of rancidity [5]. However,
it was the identification of vitamins A, C, and E as antioxidants that
revolutionized the field and led to the realization of the importance of antioxidants
in biochemistry of living organisms [6,7] that
led to the identification of antioxidants as reducing agents that prevent
oxidation reactions, often by scavenging reactive oxygen species before they
can damage cells [8].
4. Classification of Antioxidants
Antioxidants
may also be classified as enzymatic or non-enzymatic antioxidants [9].
4.1.
Enzymatic (Endogenous)
The antioxidant enzymatic system
directly/indirectly contributes to defense against the ROS. Catalase,
superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase,
etc., are enzymatic antioxidants.
4.2.
Non-Enzymatic
These antioxidants are quite a few,
namely vitamins (A, C, E, and K), enzyme cofactors (Q10), minerals (Zn, Se,
etc.), organosulfur compounds (allium and allium sulfur), nitrogen com‐ pounds (uric acid), peptides (glutathione), and
polyphenols (flavonoids and phenolic acid)
5. Mechanism of Action
Antioxidants neutralize free radicals by
donating one of their electrons, which ends the electron stealing reaction. Antioxidants
have been reported to work through single or combined mechanisms, namely, free
radical scavenging, reducing activity, complexing of pro-oxidant, scavenging
lipid peroxyl radicals, and quenching of singlet oxygen [9].
Two principle mechanisms in which antioxidants scavenge
free radical are:
1. Chain-breaking mechanism by which the
primary antioxidant donates an electron to the free radical present in the
systems, or it simply decays into a harmless product. These antioxidants target
free radicals and disrupt the chain reaction in the oxidation propagation
phase. These make up most antioxidants in the industry [1].
2. Preventive antioxidant: These antioxidants block the
formation of free radicals. This group includes metal chelators, which add to
the efficacy of secondary or chain-terminating antioxidants. It prevents
oxidation by reducing the rate of chain initiation. They can also prevent
oxidation by stabilizing transition metal radicals such as copper and iron [10].
6.
Beneficial Effects of Antioxidants
6.1. Protect Against Heart Disease
The American Heart
Association recommends a diet high in fruits, vegetables and other foods that
contain antioxidants to help fight cardiovascular disease. They do not
recommend antioxidant supplements, however, because there is no scientific
evidence to support the idea that they have any beneficial effect on heart
disease [11].
6.2. Protect Against Cancer
Lycopene
is concentrated in tomato soups, sauces, tomato paste and other tomato
products, and is also available in smaller amounts in fresh tomatoes,
watermelon and pink grapefruit. Cancers of the mouth, pharynx, esophagus,
stomach, colon and rectum can be prevented by lycopene and lutein may help
decrease your risk of macular degeneration.
6.3. Boost Immunity
Vitamin
C’s ability to reduce the severity of the common cold is indicative of its
effect on the immune system, according to experts at the Cleveland Clinic. Most
fruits and vegetables provide some Vitamin C. Citrus fruits, kiwi, tomatoes and
sweet peppers are particularly good sources.
6.4. Fight Aging
While
it has not been shown that antioxidants actually increase anyone’s lifespan,
they do protect against some of the degenerative effects on the body of age-related
diseases that can lead to early death. Studies on laboratory animals at the
U.S. Agricultural Research Service suggest that a diet high in antioxidants,
especially those found in blueberries, strawberries and spinach may also help
fight the loss of brain function associated with aging
Eating
a diet that includes a variety of fresh, deeply colored fruits and vegetables,
such as broccoli, spinach, tomatoes, sweet peppers, carrots, mangoes, kiwi,
berries and cantaloupe and other plant foods, such as grains, legumes (beans,
lentils, and split peas) and nuts, is the safest and most effective way to
boost your antioxidant supply and reap the health benefits these substances may
convey [12].
7.
Why Are They Used in Foods?
·
To
Control Lipid Oxidation
ROS attack unsaturated
fatty acids which contain multiple double bonds and methylene groups.
Antioxidants scavenge
radical and terminate chain reaction.
·
To
Minimize Protein Modification
ROS cause protein
modification by nitration or chloration of amino acids.
Antioxidants scavenge
O2-. And inhibit the
formation of radicals causing nitration and chloration.
8.
Free Radicals
They have unpaired electrons and are extremely reactive and are
capable of initiating chain reactions that destabilize other molecules and
generate free radicals. These free radicals are also termed as reactive oxygen
species or ROS and create a homeostatic imbalance that generates oxidative
stress and causes cell death and tissue injury. Free radicals are known to be
formed as a result of environmental pollution, stress, cigarette smoke, UV
Light, ionizing radiations, and xenobiotics. Toxic effect of the free radicals
causes oxidative stress and results in the pathogenesis of diseases [13].
9. Ros
are Generated by a Number of Pathways
Most
of the oxidants produced by cells occur as:
1.
A
consequence of normal aerobic metabolism: approximately 90% of the oxygen
utilized by the cell is consumed by the mitochondrial electron transport
system.
10.
Molecular Damage Induced by Free Radicals
All the biological molecules present in our body are at risk of
being attacked by free radicals. Such damaged molecules can impair cell
functions and even lead to cell death eventually
resulting in diseased states [15].
10.1.
Lipids and
Lipid Peroxidation
Membrane lipids present in subcellular organelles are highly
susceptible to free radical damage. Lipids when reacted with free radicals can
undergo the highly damaging chain reaction of lipid peroxidation (LP) leading
to both direct and indirect effects. During LP a large number of toxic
byproducts are also formed that can have effects at a site away from the area
of generation, behaving as ‘second messengers’. The damage caused by LP is
highly detrimental to the functioning of the cell [16].
10.2.
Carbohydrates
Free radicals such as •OH react with carbohydrates by randomly
abstracting a hydrogen atom from one of the carbon atoms, producing a carbon-centered
radical. This leads to chain breaks in important molecules like hyaluronic
acid. In the synovial fluid surrounding joints, an accumulation and activation
of neutrophils during inflammation produces significant amounts of oxyradicals,
that is also being implicated in rheumatoid arthritis.
10.3.
DNA
Oxidative damage to DNA is a result of interaction of DNA with ROS
or RNS. Free radicals such as •OH and H• react with DNA
by addition to bases or abstractions of hydrogen atoms from the sugar moiety.
The C4-C5 double bond of pyrimidine is particularly sensitive to attack by •OH,
generating a spectrum of oxidative pyrimidine damage products, including
thymine glycol, uracil glycol, urea residue, 5-hydroxydeoxyuridine,
5-hydroxydeoxycytidine, hydantoinand others. Similarly, interaction of •OH
with purines will generate 8-hydroxydeoxyguanosine (8-OHdG), 8- hydroxydeoxyadenosine,
formamidopyrimidines and other less characterized purine oxidative products [17].
10.4.
Proteins
Oxidation of proteins by ROS/RNS can generate a range of stable as
well as reactive products such as protein hydro peroxides that can generate
additional radicals particularly upon interaction with transition metal ions. Although
most oxidised proteins that are functionally inactive are rapidly removed, some
can gradually accumulate with time and thereby contribute to the damage
associated with ageing as well as various diseases. Lipofuscin, an aggregate of
per oxidized lipids and proteins accumulates in lysosomes of aged cells and
brain cells of patients with Alzheimer’s disease [18].
11. Antioxidant
Protection
To
protect the cells and organ systems of the body against reactive oxygen
species, humans have evolved a highly sophisticated and complex antioxidant
protection system. It involves a variety of components, both endogenous and
exogenous in origin, that function interactively and synergistically to
neutralize free radicals. Epidemiological researches
strongly suggest that foods containing antioxidants and scavengers have a
potential protective effect against disorders caused by ROS.
These
components include|:
1.
Nutrient-derived antioxidants like ascorbic acid (vitamin C), tocopherols and
tocotrienols (vitamin E), carotenoids, and other low molecular weight compounds
such as glutathione and lipoic acid.
2. Antioxidant
enzymes, e.g., superoxide dismutase, glutathione peroxidase, and glutathione
reductase, which catalyze free radical quenching reactions.
3. Metal binding
proteins, such as ferritin, lactoferrin, albumin, and ceruloplasmin that
sequester free iron and copper ions that are capable of catalyzing oxidative
reactions.
12.
Concept of Oxidative Stress
The term is used to describe the condition of oxidative damage resulting
when the critical balance between free radical generation and antioxidant
defenses is unfavorable [19]. Oxidative stress, arising as a result of an imbalance between
free radical production and antioxidant defenses, is associated with damage to
a wide range of molecular species including lipids, proteins, and nucleic acids
[20].
Short-term oxidative stress may occur in tissues injured by
trauma, infection, heat injury, hypertoxia, toxins, and excessive exercise. These
injured tissues produce increased radical generating enzymes (e.g., xanthine
oxidase, lipogenase, cyclooxygenase) activation of phagocytes, release of free
iron, copper ions, or a disruption of the electron transport chains of oxidative
phosphorylation, producing excess ROS. The initiation, promotion, and
progression of cancer, as well as the side-effects of radiation and
chemotherapy, have been linked to the imbalance between ROS and the antioxidant
defense system. ROS have been implicated in the induction and complications of
diabetes mellitus, age-related eye disease, and neurodegenerative diseases such
as Parkinson’s disease [21].
13. Oxidative Stress Test
In
this advanced materialistic life, monitoring the levels of free radicals and
oxidative stress is important in case of clinical practice. FORD (Free Oxygen
Radicals Defense) is an easy, cheap and reliable diagnostic device to monitor
oxidative stress [22,23]. It discriminates the
high risk of oxidative damage on sick or healthy individuals, monitoring with
precise laboratory parameters in the clinical situation at the baseline and in
the follow-up of a medical prescription.
14.
Ford (Free Oxygen Radicals Defense)
It
is a colorimetric test based on the influence of antioxidants present in plasma
to reduce the activity of free radicals. The principle of the assay is that at
an acidic pH (5.2) and in the presence of a suitable oxidant solution (FeCl3), 4-aminon, n- diethylaniline, the FORD
chromogen, can form a stable and colored radical cation.
Antioxidant
molecules (AOH) present in the sample which are able to transfer a hydrogen atom
to the FORD chromogen radical cation, reduce it, quenching the color and
producing a discoloration of the solution which is proportional to their concentration
in the sample. This instrument will be helpful in understanding the problem of
the individual bioavailability of each antioxidant molecule which can be monitored
during the administration, with a pre-post measure of the oxidative balance. In
order to achieve the evidence of the oxidative background related to the
outcome of specific symptoms and diseases, epidemiological studies can be encouraged,
and the role of nutrition and targeted antioxidant therapy can be better
defined [19].
15. Pro-oxidants
Pro-oxidants
are defined as chemicals that induce oxidative stress, usually through the formation
of reactive species or by inhibiting antioxidant systems. Free radicals are
considered pro-oxidants, but sometimes, antioxidants can also have pro-oxidant
behavior. Vitamin C is a potent antioxidant, but it can also become a
pro-oxidant when it combines with iron and copper reducing Fe3+ to Fe2+
(or Cu3+ to Cu2+), which in turn reduces hydrogen peroxide to
hydroxyl radicals [24].
α-Tocopherol
is a powerful antioxidant, but in high concentrations, it can become a
prooxidant. When vitamin E reacts with a free radical, it becomes a radical
itself, and if there is not enough ascorbic acid for its regeneration, it will
remain in this highly reactive state and support the autoxidation of linoleic
acid [25].
Although
not much evidence is found, it is proposed that carotenoids can also display
prooxidant effects especially through autoxidation in the presence of high
concentrations of oxygen-forming hydroxyl radicals [26].
Flavonoids may also serve as pro-oxidant [27].
16. Pro-oxidant Effect of Antioxidant Under Certain Conditions
Antioxidants also have the potential to act as prooxidants under
certain conditions. For example, ascorbate, in the presence of high concentration
of ferric iron, is a potent potentiator of lipid peroxidation. Recent studies
suggest that ascorbate sometimes increase DNA damage in humans.
Recent mechanistic studies on the early stage of LDL oxidation
show that the role of vitamin E is not simply that of a classical antioxidant. Unless
additional compounds are present, vitamin E can have antioxidant, neutral or
prooxidant activity. Beta-carotene also can behave as a prooxidant in the lungs
of smokers.
The paradoxical role (pro-oxidant effect) of antioxidants is also
directly related to the recently described ‘redox signaling’ of the
antioxidants. The functional role of many antioxidants depends on redox
cycling. For example, the best-described intracellular antioxidant vitamin E
supplementation in the face of infarcted myocardium exerted prooxidant effects
resulting in the rupture of the plaques. When a cell is attacked by environmental
stress, the cell’s defense is lowered because of massive generation of ROS. The
cell immediately responds to this stress by upregulating its antioxidant
defense. During the induction process ROS function as signaling molecules.
It should be easily understood that in these pathophysiological
conditions even though the antioxidants are lowered and supplementation of the
antioxidants are warranted, the antioxidants should be harmful because they will
prevent the function of the ROS to perform signal transduction to induce
intracellular antioxidants [15].
17. Antioxidant Therapy
It is
a way of treating patients with a variety of natural vitamins and nutritional
elements in order to try to limit some kinds of degenerative conditions. Antioxidant
therapy may include dietary changes as well as specific dietary supplements.
18. Antioxidants in Cosmetics
Antioxidants
are very useful active ingredients for the manufacturing of cosmetics. Antioxidants
are useful in two ways: On the one hand they prevent degradation of natural
ingredients (proteins, sugars, lipids) in the cosmetic product. On the other hand,
antioxidants protect the skin cells from being damaged and slow down the aging
process.
18.1.
Skin Care
Antioxidants
protect the skin against sun damage and skin
cancer. And they may actually reverse some of the
discoloration and wrinkles associated
with aging. These antioxidants work by speeding up the skin's natural repair
systems and by directly inhibiting further damage
18.2.
Hair Care
Antioxidants
are extremely beneficial in the prevention of hair loss as well as stimulating
new, healthy hair growth. “Some of the most powerful ones are green tea,
blueberries and grape seed extract.” More and more hair products are
incorporating these ingredients into their formulas
19. Antioxidant Therapy: In
Animals
Dog
and cat foods, which often contain significant levels of fat, are especially
susceptible to oxidation. The most common artificial antioxidants used in the
pet food industry are ethoxyquin, butylated hydroxytoluene (BHT), and butylated
hydroxyanisole (BHA). Commonly used natural antioxidants include tocopherols
(vitaminE), ascorbic acid (vitamin C), citric acid, and rosemary. Ethoxyquin,
which has been approved for use in animal feeds for over 30 years. It is
currently allowed in dog foods at levels of up to 150 parts per million (ppm),
or 0.015%. [28].
20. Assays of Determination
TAC
assays may be broadly classified as electron transfer (ET)- and hydrogen atom
transfer (HAT)-based assays
20.1.
The
DPPH (4-2,2-Diphenyl-1-Picrylhydrazyl)
Method
A rapid, simple and
inexpensive method to measure antioxidant capacity of food involves the use of
the free radical 2,2-Diphenyl-1-picrylhydrazyl (DPPH). DPPH is widely used to
test the ability of compounds to act as free radical scavengers or hydrogen
donors, and to evaluate antioxidant activity of foods. It has also been used to
quantify antioxidants in complex biological systems in recent years. The DPPH
method can be used for solid or liquid samples and is not specific to any
particular antioxidant component, but applies to the overall antioxidant
capacity of the sample. A measure of total antioxidant capacity helps
understand the functional properties of foods [29].
20.2.
The
FRAP (Ferric Reducing Antioxidant Power) Method
This
method is simple, speedy, inexpensive, and robust does not require specialized
equipment. FRAP assay also takes
advantage of electron-transfer reactions. Here, a ferric salt, Fe (III)
(TPTZ)2Cl3 (TPTZ) 2,4,6-tripyridyls-triazine), is used as an oxidant. This method relies on the reduction by the antioxidants, of
the complex ferric ion-TPTZ (2,4,6-tri(2-pyridyl)- 1,3,5-triazine). The binding
of Fe2+ to the ligand creates a very intense navy blue color. The absorbance
can be measured to test the amount of iron reduced and can be correlated with
the amount of antioxidants. Trolox or ascorbic acid were used as references [29].
20.3.
The ORAC (Oxygen Radical Absorption
Capacity) Assay
This procedure is used to
determine antioxidant capacities of fruits and vegetables. This method measures the antioxidant scavenging activity
against the peroxyl radical, induced by 2,2’-azobis-(2-amidino-propane)
dihydrochloride (AAPH), at 37°C. Fluorescein was used as the fluorescent probe. The loss
of fluorescence was an indicator of the extent of the decomposition, from its
reaction with the peroxyl radical. The advantage of the AUC approach is
that it implies equally well for both antioxidants that exhibit distinct lag
phase and those that have no lag phases. ORAC assay has been broadly applied in
academy and in the food and dietary supplement industries as a method of choice
to quantify AOC [29].
20.4.
ORAC Values
One way of checking the antioxidant ability of vegetables and
fruits is measuring its ORAC value or oxygen radical absorbance capacity. Some
fruits/vegetables with their ORAC values/100 g in (brackets) are raisins
(2830), black berries (2036), strawberries (1540), oranges (750), grapes (739),
cherries (670), spinach (1260), beets (840), onion (450) and eggplant (390).
Intake of fruits and vegetables with ORAC values between 3000 and 5000 per day
is recommended to have significant impact of the beneficial effect of
antioxidants [30].
20.5.
The
HORAC (Hydroxyl Radical Averting Capacity) Assay
This technique
relies on the measurement of the metal-chelating activity of antioxidants,
under the conditions of Fenton-like reactions. The method uses a Co(II) complex
and hence evaluates the protecting ability against the formation of hydroxyl
radical. Fluorescein is incubated with the sample to be analysed, then the
Fenton mixture (generating hydroxyl radicals) was added. The initial
fluorescence was measured, after which the readings were taken every minute
after shaking. Gallic acid solutions were used for building the standard curve [31,32].
20.6.
The
TRAP (total peroxyl radical trapping antioxidant parameter) Assay
The luminol-enhanced
chemiluminescence (CL) was exploited to monitor the reactions involving the
peroxyl radical. The CL signal is driven by the production of luminol derived
radicals, resulted from the thermal decomposition of AAPH. The TRAP value was
determined from the duration of the time period during which the sample
quenched the chemiluminiscence signal, due to the presence of antioxidants [32,33].
20.7.
The
Lipid Peroxidation Inhibition Assay
The lipid
peroxidation inhibition assay method uses a Fenton-like system (Co(II) + H2O2), to induce lipid (e.g. fatty acid)
peroxidation. α-linolenic acid was chosed as a model
substrate. It was mixed with the analysed sample, as well as with the
Fenton-like mixture, to induce lipid peroxidation. After the end of the
incubation, the concentration of thiobarbituric acid-reactive substances (TBARS)
was measured, as the index of lipid peroxidation. Lipid peroxidation was
expressed in nmoles of TBARS per 1 ml of mixture α-linolenic
acid/analysed sample [32,34].
20.8.
The
PFRAP (potassium ferricyanide reducing power) Method
An absorbance
increase can be correlated to the reducing ability of antioxidants/antioxidant
extracts. The compounds with antioxidant capacity react with potassium
ferricyanide, to form potassium ferrocyanide. The latter reacts with ferric
trichloride, yielding ferric ferrocyanide, a blue coloured complex, with a
maximum absorbance at 700nm [35,36].
20.9.
The
CUPRAC (cupric reducing antioxidant power) Assay
The standard
antioxidants or extracts are mixed with CuSO4 and
neocuproine. After 30 min, the absorbance was measured at 450 nm. In the assay,
Cu(II) is reduced to Cu(I) through the action of electron donating
antioxidants. Results are expressed in milligrams of Trolox per liter of
extract [33].
21.
Current Scenario
Combinations of antioxidants are proving to be
better than using them separately, combination treatments are also becoming
more popular individually. These have shown to include a large variety of
antioxidant compounds such as carotenoids, polyphenols, vitamins and
polysaccharides
Antioxidant therapy in cows - Improves immune
response which decreases mastitis in dairy cows and infectious disease
incidences arising in stressed cattle following shipping
22.
Newer and Novel Approaches to Reduce Free Radical
Damage and Future Prospects
·
Attention needs to be drawn on focusing more on
disease-specific, target-directed, highly bioavailable antioxidants.
There are several novel approaches in the study of free
radicals/antioxidants for the improvement of human health. The total evidences
from experimental, clinical, and epidemiological studies support the notion
that consumption of foods obtaining high levels of dietary antioxidants, in
addition to exerting several health benefits, may prevent or reduce the risk of
oxidative stress.
Targeted delivery of antioxidants to mitochondria is a new
exciting field of research that seeks to concentrate antioxidants on the inner
membrane of mitochondria in order to protect against mitochondrial oxidative
stress [37].
Antioxidant gene therapy has also recently been proposed as a
treatment strategy that can overcome the problem of poor availability of the
antioxidant at its target [38].
Development of genetically engineered plants, to yield
vegetables with higher level of certain compounds is another approach to
increase antioxidant availability. Tomatoes with up to 3 times lycopene
concentration as well as with longer shelf life were developed [30].
23.
Conclusion
Several
decades have passed since the idea of antioxidant therapy was introduced for
the first time. The field of antioxidants turned out to be much more
challenging than what was presumed in the beginning. Much effort has been
directed to the study of the efficacy of different antioxidants in human
diseases, but unfortunately the products of this long process have not been
satisfactory.
However, the lack of clear cut
success in clinical trials does not disprove the crucial role of oxidative
stress in diseases. We have learned many things along this way. Once we apply
our experience to select the right disease and the right population, design optimized,
and highly bioavailable antioxidants directed at specific and appropriate
targets and choose optimal treatment times and durations, useful therapeutics
could emerge for various diseases.
|
1. |
Carotenoids (a form of vitamin A)
|
Apricots, peaches, broccoli, pumpkin, cantaloupes, carrots, spinach and sweet potatoes |
|
2. |
Beta-Carotene |
Fruits, grains, oils and vegetables (carrot, green plants, spinach) |
|
3. |
Lycopene
|
Tomatoes |
|
4. |
Alpha Tocopherol (Vitamin E)
|
Nuts & seeds, whole grains, green leafy vegetables, vegetable oil and liver oil, eggs, poultry meat. |
|
5. |
Ascorbic acid (Vitamin C) |
Citrus fruits like oranges and lime etc, green peppers, broccoli, green leafy vegetables, strawberries and tomatoes
|
|
6. |
Selenium
|
Fish & shellfish, red meat, liver, yeast, grains, eggs, chicken and garlic |
|
7. |
Flavonoids
|
Green tea, grapes, apple, cocoa, berries, onion, broccoli.
|
|
8. |
Resveratrol
|
Grapes, red wine, purple grape juice, peanuts, and some berries. |
|
Most Commonly Known Antioxidants & Their Food Sources. [10] |
||
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