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Natural and synthetic antioxidants Section C-Review
Eur. Chem. Bull. 2017, 6(8), 365-375 DOI: 10.17628/ecb.2017.6.365-375
365
ANTIOXIDANTS: AN OVERVIEW ON THE NATURAL AND
SYNTHETIC TYPES
Emad M. Atta[a,b]*, Nawal H. Mohamed[c,d] and Ahmed A. M. Abdelgawad[d]
Keywords: Oxidants, antioxidants, definition, natural and synthetic types, assay methods.
Antioxidants were used to prevent oxidation process in foods which lead to rancidity and browning, DNA oxidation and have many
positive physiological effects in human. The concentration and the absorption mechanism of natural antioxidants are important in obtaining
the maximum beneficial effect. The sources of antioxidants must be carefully considered to maximize absorption and avoid the toxicity of
higher concentration of synthetic groups. A general lack of information about antioxidants indicates by a survey of the general public. An
organized effort to educate individuals about foods rich in natural antioxidants and the ability to recognize the major synthetic antioxidants
on food labels would be highly beneficial, though more research needs to be done to fully understand their physiological effects.
* Corresponding Authors
E-Mail: emadata@yahoo.com
[a] Chemistry Department, Faculty of Science, Jazan University,
Jazan, KSA
[b] Genetic Engeneering. and Biotechnology Research Institute,
University of Sadat City, Egypt
[c] Chemistry Department, Faculty of Science, Girls’ Section,
Jazan University, Jazan, KSA
[d] Aromatic and Medicinal Plants Department, Desert Research
Center, Cairo, Egypt
Introduction
Antioxidants go through several processes before they can
have consumed by the people. Researchers in the middle of
the twenty-first century after doing many researches found
that life span of people increases by the normal consumption
of anti-oxidants and also it prevents several fatal diseases.
At the end of 19th century, antioxidants are used for several
industrial processes like prevention of metal corrosion,
rubber vulcanization. The scientists found that these
substances or anti-oxidants protects the metal from
corrosion and limited the oxidation of the metals.1-2
Antioxidants are widely used as an ingredient in dietary
supplement for promoting good health and preventing
diseases like cancer, cardiovascular disease. In addition,
they are also used as preservatives for foods. This indeed
happened in the mid. 20th century. It all started with the
attempts by scientists to extend the life of foods. By
combining antioxidants with foods which have high
unsaturated fat, the tests were able to prevent the onset of
rancidity - a nasty process by which the unsaturated fats
break down and produce a rancid-like smell and taste.3 As
this process continued; new information was brought to light,
it was quickly discovered that a few of the key and vital
vitamins - essential in the human diet – were actually able to
be classified as antioxidants too. This meant that over the
past 1000 years, people had been consuming antioxidants on
a daily basis.4
The aim of this review is to explore the different types of
natural and synthetic antioxidants, the suggested mechanism
and physiological effects of each type as well, in addition to
the potential health risks associated with consuming the
synthetic antioxidants. On the other hand, an overview on
the definitions, uses, popular methods to assay antioxidant
activity was stated.
Oxidation of foods
Oxidation process
Most foods are made up of several organic compounds
that can easily undergo oxidation. Lipids (such as fats, oils,
and waxes) in general have the greatest tendency to lose
electrons. Auto-oxidation of lipids in food Triggered by
exposure to light, heat, ionizing radiation, metal ions or
metallo-protein catalysts can have a deteriorating effect on
the food colour, flavour, texture, quality, and safety. Fats
contained in food are chemically composed of triglycerides
and oxidation leading to the rancidity of foods occurs at the
unsaturated sites of the triglycerides.5
Oxidants
The most common oxidants in biological systems are free
radicals. Free radicals are atoms, molecules or ions with
unpaired electrons that are highly unstable and active
towards chemical reactions with other molecules. An
unpaired electron in these free radicals, causes them to seek
out and capture electrons from other substances in order to
stabilize themselves. Although the initial attack causes the
odd electron to be paired, another free radical is formed in
the process, causing a chain reaction to occur.6
In the biological systems, the free radicals are often
derived from oxygen, nitrogen and sulphur molecules. These
free radicals are parts of groups of molecules called reactive
oxygen species (ROS), reactive nitrogen species (RNS) and
reactive sulphur species (RSS). For example, ROS includes
free radicals such as superoxide anion (O2-•), perhydroxyl
radical (HO2•), hydroxyl radical (·OH), nitric oxide and
other species such as hydrogen peroxide(H2O2), singlet
oxygen (O2), hypochlorous acid (HOCl) and peroxynitrite
Natural and synthetic antioxidants Section C-Review
Eur. Chem. Bull. 2017, 6(8), 365-375 DOI: 10.17628/ecb.2017.6.365-375
366
(ONOO-).7 RNS are derived from nitric oxide through the
reaction with O2-• to form ONOO-. RSS are easily formed
from thiols by reaction with ROS.8 ROS are produced during
cellular metabolism and functional activities.
Formation of free radicals in cells
Free radicals can be formed in 3 ways, (i) by homolytic
cleavage of covalent bond of a normal molecule, with each
fragment retaining one of the paired electrons, (ii) by loss of
single electron from normal molecule and (iii) by addition of
a single electron to a normal molecule. They are constantly
being generated in vivo.9
Four endogenous sources appear to account for most of
the oxidants produced by cells.
(i) Normal aerobic respiration in which
mitochondria consume O2, reduces it by
sequential steps to produce O2, H2O2, and -OH as
byproducts.
(ii) Bacteria or virus infected cells get destroyed by
phagocytosis with an oxidative burst of nitric
oxide (NO), O2-, H2O2 and OCl.
(iii) Peroxisomes produce H2O2 as a byproduct of
fatty acid and other lipid molecular degradation,
which is further degraded by catalase. Evidence
suggests that, certain conditions favor escape of
some of the peroxide from degradation,
consequently releasing it into other
compartments of the cell and increasing
oxidative stress leading to DNA damage.
(iv) Animal Cytochrome P450 enzymes are one of the
primary defense systems that provides protection
against natural toxic chemicals from plants, the
major source of dietary toxins. Even these
enzymes are protective against acute toxic effects
from foreign chemicals, yet they may generate
some oxidative byproducts that damage DNA.10-
13
Effect of oxidants on body tissue
Excessive amounts of free radicals can have deleterious
effects on many molecules including protein, lipid, RNA
and DNA since they are very small and highly reactive.
ROS can attack bases in nucleic acids, amino acid side
chains in proteins and double bonds in unsaturated fatty
acids, in which ·OH is the strongest oxidant. ROS attacking
macromolecules is often termed oxidative stress. Cells are
normally able to defend themselves against ROS damage
through the use of intracellular enzymes to keep the
homeostasis of ROS at a low level.
However, during times of environmental stress and cell
dysfunction, ROS levels can increase dramatically, and
cause significant cellular damage in the body. Thus,
oxidative stress significantly contributes to the pathogenesis
of inflammatory disease, cardiovascular disease, cancer,
diabetes, Alzheimer’s disease, cataracts, autism and aging.14-
17 In order to prevent or reduce the ROS induced oxidative
damage, the human body and other organisms have
developed an antioxidant defense system that includes
enzymatic, metal chelating and free radical scavenging
activities to neutralize these radicals after they have formed.
In addition, intake of dietary antioxidants may help to
maintain an adequate antioxidants status in the body.
Antioxidants
In foods, antioxidants have been defined as ‘substances
that in small quantities are able to prevent or greatly retard
the oxidation of easily oxidisable materials such as fats,18
therefore, in food science antioxidants are usually equated
with chain-breaking inhibitors of lipid peroxidation, but not
exclusively so. Many antioxidants have been studied and are
used in a wide range of foods including beverages.
Therefore, for foods and beverages, antioxidants are
molecules that can be equated with the protection of
macromolecules from oxidation.19 In biological systems the
accepted definition is that antioxidant is any substance that,
when present at low concentrations compared to those of an
oxidisable substrate, significantly delays or prevents
oxidation of that substrate.20-21 This is a broader definition
encompassing many vulnerable macromolecules (e.g. DNA,
lipids and proteins) that can be affected by oxidation. In
biological terms, it is accepted that any molecule that can
retard or prevent the action of oxidants could be considered
to be an antioxidant.22 Such a broad definition means that
compounds that inhibit specific oxidizing enzymes, react
with oxidants before they damage molecules, sequester
dangerous metal ions or even repair systems such as iron
transport proteins, can fit the definition. Antioxidants can
also be defined as substances that trap harmful forms of
oxygen and prevent them from damaging cells.23
Mechanistic definitions of antioxidants are usually focused
on the ability to be a hydrogen donor or an electron donor.
Many of the frequently cited assays of antioxidant capacity
can be broadly categorized as either hydrogen transfer
assays or single electron transfer reaction based assays.
These assays measure the radical scavenging capacity or the
reducing ability, respectively, not the preventative
antioxidant capacity of the sample.24
Antioxidants process
Antioxidants block the process of oxidation by
neutralizing free radicals. In doing so, the antioxidants
themselves become oxidized. How do they work? The two
possible pathways are chain-breaking and preventive.25
Chain-breaking: When a free radical release or abstracts
an electron, a second radical is formed. This molecule then
turns around and does the same thing to a third molecule,
continuing to generate more unstable products. The process
continues until termination occurs, either the radical is
stabilized by a chain-breaking antioxidant such as -
carotene and vitamins C and E, or it simply decays into a
harmless product.
Preventive: Antioxidant prevents oxidation by reducing
the rate of chain initiation. That is, by scavenging initiating
radicals, such antioxidants can thwart an oxidation chain
from ever setting in motion. They can also prevent oxidation
by stabilizing transition metal radicals such as copper and
iron.
Natural and synthetic antioxidants Section C-Review
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Mechanisms
If a compound inhibits the formation of free alkyl
radicals in the initiation step, or if the chemical compound
interrupts the propagation of the free radical chain, the
compound can delay the start or slow the chemical reaction
rate of lipid oxidation. The initiation of free radical
formation can be delayed by the use of metal chelating
agents, singlet oxygen inhibitors and peroxide stabilizers.
The propagation of free radical chain reaction can be
minimized by the donation of hydrogen from the
antioxidants and the metal chelating agents.26
(1) R:H + O::O + Initiator → R• + HOO•
(2) R• + O::O → ROO•
(3) ROO• + R:H → ROOH + R•
(4) RO:OH → RO• + HO•
(5) R::R + •OH → R:R-O•
(6) R• + R• → R:R
(7) R• + ROO• → ROOR
(8) ROO• + ROO• → ROOR + O2
(9) ROO• + AH → ROOH + A•
(10) ROO• + A• → ROOA.
Scheme 1. Mechanism of antioxidants’ action.
Antioxidant Defenses
Antioxidant means "against oxidation." Antioxidants work
to protect lipids from per oxidation by radicals. Antioxidants
are effective because they are willing to give up their own
electrons to free radicals. When a free radical gain the
electron from an antioxidant it no longer needs to attack the
cell and the chain reaction of oxidation is broken.27 After
donating an electron an antioxidant becomes a free radical
by definition. Antioxidants in this state are not harmful
because they have the ability to accommodate the change in
electrons without becoming reactive. The human body has
an elaborate antioxidant defense system. Antioxidants are
manufactured within the body and can also be extracted
from the food which humans eat such as fruits, vegetables,
seeds, nuts, meats, and oil.
Types of Antioxidants
Antioxidant system includes, antioxidant enzymes (e.g.,
SOD, GPx and reductase, CAT, etc.), nutrient-derived
antioxidants (e.g., ascorbic acid, tocopherols and
tocotrienols, carotenoids, glutathione and lipoic acid), metal
binding proteins (e.g., ferritin, lactoferrin, albumin, and
ceruloplasmin) and numerous other antioxidant
phytonutrients present in a wide variety of plant foods.
Dietary antioxidants, such as water-soluble vitamin C and
phenolic compounds, as well as lipid-soluble vitamin E and
carotenoids, present in vegetables contribute both to the first
and second defense lines against oxidative stress.28
Natural antioxidants
Natural antioxidant system is sorted in two major groups,
enzymatic and non- enzymatic.
Non-enzymatic antioxidants: Non-enzymatic antioxidants
include direct acting antioxidants, which are extremely
important in defense against oxidation stress. Most of them,
including ascorbic and lipoic acid, polyphenols and
carotenoids, are derived from dietary sources. The cell itself
synthesizes a minority of these molecules. Indirectly acting
antioxidants mostly include chelating agents and bind to
redoxmetals to prevent free radical generation.29
Vitamin E is a generic description for all tocopherol (Toc)
and tocotrienol (Toc-3) derivatives. Tocopherols have a
phytyl chain, while tocotrienols have a similar chain but
with three double bonds at positions 3',7' and 11'. Both
tocopherols and tocotrienols have four isomers, designated
as α-, β-, γ- and δ-, which differ by the number and position
of methyl groups on the chroman ring.30 All of these
molecules possess antioxidant activity, although -
tocopherol (α-Toc) is chemically and biologically the most
active.31-32 α-Tocopherol is the major vitamin E in vivo and
exerts the highest biological activity. Tocopherols are
present in polyunsaturated vegetable oils and in the germ of
cereal seeds, whereas tocotrienols are found in the aleurone
and subaleurone layers of cereal seeds and in palm oils.
Figure 1. Structure of vitamin E.
It has been reported that α-Toc-3 possessed 40- to 60-fold
higher antioxidant activity than α-Toc against ferrous
iron/ascorbate- and ferrous iron/NADPH-induced lipid
peroxidation in rat liver microsomes33 and that α-Toc-3
exhibited greater peroxyl radical scavenging potency than α-
Toc in liposomal membranes.34
The antioxidant reaction of α-tocopherol is not a reaction
with oxygen. Many molecules react with oxygen, but they
do so without being antioxidants. β-Carotene, for example,
Natural and synthetic antioxidants Section C-Review
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368
readily reacts with oxygen, but it is by no means an efficient
antioxidant.35 The basis of an antioxidant reaction is not the
removal of oxygen but the interception of the autoxidation
radical chain process which is not perpetuated by oxygen
but by the fatty acid.
α-Tocopherol reacts with fatty acid peroxyl radicals, the
primary products of lipid peroxidation, and intercepts the
chain reaction.36 What makes α-tocopherol such a highly
efficient antioxidant is (i) that it reacts with the peroxyl
radical extremely fast, much faster than to allow for the
peroxyl radical to do any other reactions; (ii) it takes away
the radical character from the oxidizing fatty acid and
prevents it from further radical reactions; (iii) in the
antioxidant reaction, α-tocopherol is turned into a fairly
stable radical. Under normal circumstances, it will only
react with another radical (either a tocopheroxyl radical or a
fatty acid peroxyl radical) to form stable, non-radical
products. In this setting, α-tocopherol is the most powerful
lipid soluble antioxidant known, and only recently novel
synthetic antioxidants have been developed that surpass α-
tocopherol’s antioxidant capacity.37 Chemically, abstraction
of the 6-OH hydrogen yields a tocopheroxyl radical.
Tocopherol can be restored by reduction of the tocopheroxyl
radical with redox-active reagents like vitamin C (ascorbate)
or ubiquinol.38-42 In homogeneous solution phase
autoxidation, the tocopheroxyl radical will react with a
second peroxyl radical to give non radical products. This
second reaction leads to the destruction of a tocopherol as an
antioxidant. Thus, one molecule of a-tocopherol can
terminate two autoxidation chains.
The main source for dietary uptake of vitamin E is plant
food (vegetables, fruits, seeds, and seed oils). Sunflower
seeds, olive oil, and almonds are rich sources of α-
tocopherol. While other seeds and seed oils generally
contain more γ-tocopherol than α-tocopherol, the opposite is
true for green leaves. β-Tocopherol and δ-tocopherol are the
least abundant, and so, in general, are the different
tocotrienols.43
Vitamin C (ascorbic acid and ascorbate) is a six-carbon
lactone which is synthesized from glucose by many animals.
Vitamin C is a water-soluble vitamin. As such, it scavenges
free radicals that are in an aqueous (water). When there is
insufficient vitamin C in the diet, humans suffer from the
potentially lethal deficiency disease scurvy.44
Vitamin C is an electron donor (reducing agent or
antioxidant), and probably all of its biochemical and
molecular functions can be accounted for by this function.
Vitamin C acts as an electron donor for 11 enzymes.45-46
Gastric juice vitamin C may prevent the formation of N-
nitroso compounds, which are potentially mutagenic.47 High
intakes of vitamin C correlate with reduced gastric cancer
risk,48 but a cause and effect relationship has not been
established. Vitamin C protects low-density lipoproteins ex
vivo against oxidation and may function similarly in the
blood.49
Vitamin C plays an important role in the production of
collagen. Collagen gives your skin elastic properties. As
people get older, their skin contains lower levels of collagen.
Most anti-aging creams, therefore, include plenty of Vitamin
C. This keeps the skin young and healthy by improving
elasticity.
Scheme 2. Formation of ascorbate radical.
A common feature of vitamin C deficiency is anaemia.
The antioxidant properties of vitamin C may stabilize folate
in food and in plasma, and increased excretion of oxidized
folate derivatives in human scurvy was reported.50 Vitamin
C promotes absorption of soluble non-haem iron possibly by
chelation or simply by maintaining the iron in the reduced
(ferrous, Fe2+) form.51-52 The effect can be achieved with the
amounts of vitamin C obtained in foods. However, the
amount of dietary vitamin C required to increase iron
absorption ranges from 25 mg upwards and depends largely
on the amount of inhibitors, such as phytates and
polyphenols, present in the meal.53 Vitamin C (ascorbate,
AscH-), for example, can donate a hydrogen atom to a free
radical molecule thereby neutralizing the free radical
(ascorbic acid, generally acts as an antioxidant by donating
hydrogen atoms from its own hydroxyl groups in order to
quench reactive radical species) and generating double
bonds in place of the lost hydrogen to make up for the lost
electron density. However, once this occurs, the Vitamin C
molecule itself is oxidized, and so it is reduced back into a
useable form of the Vitamin C molecule by a variety of
enzymes, including glutathione.
Scheme 3. Oxidation of Vitamin C.
But the ascorbic acid free radical is very stable because of
its resonance structure.54 In general, recent literature on the
interaction between vitamin C and vitamin E has provided
strong support for the non-enzymatic regeneration of α-
tocopherol from the α-tocopheroxyl radical, formed when α-
tocopherol scavenges a peroxyl radical (ROO•), by ascorbic
acid.
Vitamin C is found in many fruits and vegetables.55 Citrus
fruits and juices are particular important sources of vitamin
C but other fruits including cantaloupe, honeydew melon,
Natural and synthetic antioxidants Section C-Review
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cherries, kiwi fruits, mangoes, papaya, strawberries, tangelo,
watermelon, and tomatoes also contain variable amounts of
vitamin C. Vegetables such as cabbage, broccoli, Brussels
sprouts, beansprouts, cauliflower, kale, mustard greens, red
and green peppers, peas, tomatoes, and potatoes may be
more important sources of vitamin C than fruits. This is
particularly true because the vegetable supply often extends
for longer periods during the year than does the fruit supply.
-Carotene
Carotenoids are a widespread group of naturally occurring
fat-soluble colorants. In developed countries, 80-90% of the
carotenoid intake comes from fruit and vegetable
consumption. Of the more than 700 naturally occurring
carotenoids identified, only six of them (β-carotene, β-
cryptoxanthin, α-carotene, lycopene, lutein and zeaxanthin)
account for more than 95% of total blood carotenoids. β-
Carotene (BC) is a naturally occurring orange-colored
carbon-hydrogen carotenoid, abundant in yellow-orange
fruits and vegetables and in dark green, leafy vegetables.56 It
is also the most widely distributed carotenoid in foods.57 BC
undergoes trans (E) to cis (Z) isomerization,58 whereas the
(all-E)-form is the predominant isomer found in unprocessed
carotene rich plant foods.59-60
Nutrition has a significant role in the prevention of many
chronic diseases such as cardiovascular diseases (CVD),
cancers, and degenerative brain diseases.61 The consumption
of food-based antioxidants like BC seems to be useful for
the prevention of macular degeneration and cataracts.62 It is
also available in synthetic forms and is commercially
processed from substances such as palm oil and algae. BC
has potential antioxidant biological properties due to its
chemical structure and interaction with biological
membranes.63 It is well-known, that BC quenches singlet
oxygen with a multiple higher efficiency than α-
tocopherol.64 In addition, it was shown that (Z)-isomers of
BC possess antioxidant activity in vitro.65-67
The other strategy with which antioxidants prevent
oxidation is to use double bonds to donate electron density.
As the electrons in double bonds are less tightly held to the
molecule, they are more easily available for donation.
Generally, antioxidants that use this strategy are non-polar,
and contain hydrocarbon chains of moderate length. Three
prominent natural antioxidants that utilize this method are
carotene, lycopene, and vitamin A. Carotene and lycopene
have very similar mechanisms of antioxidant activity, as
both have similar chemical structures and fall into the
carotenoid family of molecules.
Scheme 4. Oxidation of carotene via the donation of an electron
from a double bond.
Phenolic antioxidants
Phenolic compounds are a large group of the secondary
metabolites widespread in plant kingdom. They are
categorized into classes depending on their structure and
subcategorized within each class according to the number
and position of hydroxyl group and the presence of other
substituents. The most widespread and diverse group of the
polyphenols are the flavonoids which are built upon C6-C3-
C6 flavone skeleton. In addition, other phenolic compounds
such as benzoic acid or cinnamic acid derivatives have been
identified in fruits and vegetables.68-69
Phenolic compounds, especially flavonoids, possess
different biological activities, but the most important are
antioxidant activity, capillary protective effect, and
inhibitory effect elicited in various stages of tumor.70-73
Phenolics are able to scavenge reactive oxygen species due
to their electron donating properties. Their antioxidant
effectiveness depends on the stability in different systems,
as well as number and location of hydroxyl groups. In many
in vitro studies, phenolic compounds demonstrated higher
antioxidant activity than vitamins and carotenoids.74-75
The major antioxidative phenolics in plants can be divided
into four general groups viz., phenolic acids (gallic,
protochatechuic, caffeic, and rosmarinic acids), diterpenes
(carnosol and carnosic acid), flavonoids (quercetin and
catechin), and volatile oils (eugenol, carvacrol, thymol, and
menthol).76 Phenolic acids generally act as antioxidants by
trapping free radicals whereas flavonoids can scavenge free
radicals and metal chelates as well.77
Many mechanisms have been proposed for polyphenol
prevention of oxidative stress and ROS/RNS generation
both in vitro and in vivo. Radical scavenging by polyphenols
is the most widely published mechanism for their
antioxidant activity. In this radical scavenging mechanism,
polyphenols sacrificially reduce ROS/RNS, such as •OH,
O2•-, NO•, or OONO- after generation, preventing damage to
biomolecules or formation of more reactive ROS.78-80 The
spatial arrangement of substituents is perhaps a greater
determinant of antioxidant activity than the flavone
backbone alone. Consistent with most polyphenolic
antioxidants, both the configuration and total number of
hydroxyl groups substantially influence several mechanisms
of antioxidant activity.81-83
Selenium
Selenium (Se) is an essential trace element and its
deficiency in humans has been linked to increased risk of
various diseases, such as cancer and heart diseases. Good
food sources of selenium include fish, shellfish, red meat,
grains, eggs and chicken. Vegetables can also be a good
source if grown in selenium-rich soils. This mineral is
thought to help fight cell damage by oxygen-derived
compounds and thus may help protect against cancer. It is
best to get selenium through foods, as large doses of the
supplement form can be toxic. The level of Se generally
depends on its level in soil.84 Selenium is a mineral, not an
antioxidant nutrient. However, it is a component of
antioxidant enzymes. Since its discovery as an important
component of antioxidant enzymes, such as glutathione
peroxidase (GPx), thioredoxinreductase (TrxR) and
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iodothyroninedeiodinases (IDD), there has been an
increased interest in the study of other Se-containing
proteins (selenoproteins) or enzymes (selenoenzymes).85
The selenoenzymes that are found to have strong
antioxidant activity include six groups of the GPx-GPx1,
GPx3, GPx4, GPx5 and GPx6. These GPx play a significant
role in protecting cells against oxidative damage from ROS
and RNS, which include superoxide, hydrogen peroxide,
hydroxyl radicals, nitric oxide and peroxynitrite.86-87 The
other essential antioxidant selenoenzymes are the TrxR
where they use thioredoxin (Trx) as a substrate to maintain a
Trx/TrxR system in a reduced state for removal of harmful
hydrogen peroxide.88-89 There are three types of TrxR that
have been identified, and these include cytosolic TrxR1,
mitochondrial TrxR2 and spermatozoa-specific TrxR,
(SpTrxR).90-91 Increasing evidence suggests that
selenoprotein may also play a significant role in antioxidant
defense system in preventing attack from harmful ROS and
RNS.92-93
Enzymatic antioxidants
Antioxidant enzymes are capable of stabilizing, or
deactivating free radicals before they attack cellular
components. They act by reducing the energy of the free
radicals or by giving up some of their electrons for its use,
thereby causing it to become stable. In addition, they may
also interrupt with the oxidizing chain reaction to minimize
the damage caused by free radicals. By reducing exposure to
free radicals and increasing the intake of antioxidant enzyme
rich foods or antioxidant enzyme supplements, our body’s
potential to reducing the risk of free radical related health
problems is made more palpable.94 Antioxidant enzymes are,
therefore, absolutely critical for maintaining optimal cellular
and systemic health.
The repair enzymes that can recreate some antioxidants
are SOD, GPx, glutathione reductase (GR), CAT and the
other metalloenzymes. SOD, CAT, and GPx constitute a
mutually supportive team of defense against ROS. While
SOD lowers the steady-state level of O2-, catalase and
peroxidases do the same for H2O2.
Scheme 5. Mechanism of action of enzymatic antioxidant.
The antioxidant enzymes–GPx, heme peroxidase, CAT,
and SOD–metabolize oxidative toxic intermediates and
require micronutrient cofactors such as selenium, iron,
copper, zinc, and manganese for optimum catalytic
activity.95
The antioxidant enzymes superoxide dismutase
(SOD), catalase (CAT) and glutathione peroxidase (GPx)
serve as the primary line of defence in destroying free
radicals. Glutathione plays several roles in the body e.g., it
improves the effectiveness of Vitamin C. SOD first reduces
(adds an electron to) the radical superoxide (O2-) to form
hydrogen peroxide (H2O2) and oxygen (O2). Catalase and
GPx then work simultaneously with the protein glutathione
to reduce hydrogen peroxide and ultimately produce water
(H2O). The oxidized glutathione is then reduced by another
antioxidant enzyme glutathione reductase. Together, they
repair oxidized DNA, degrade oxidized protein, and destroy
oxidized lipids (fat-like substances that are a constituent of
cell membranes). Various other enzymes act as a secondary
antioxidant defense mechanism to protect from further
damage.95
SOD is the antioxidant enzyme that catalyzed the
dismutation of the highly reactive superoxide anion to O2
and to the less reactive species H2O2. Peroxide can be
destroyed by CAT or GPx reactions.96-98 In humans, there
are three forms of SOD, cytosolic Cu/Zn-SOD,
mitochondrial Mn-SOD, and extracellular SOD (EC-
SOD).99-100 SOD destroys O2- by successive oxidation and
reduction of the transition metal ion at the active site in a
Ping Pong type mechanism with remarkably high reaction
rates.101 All types of SOD bind single charged anions such
as azide and fluoride, but distinct differences have been
noted in the susceptibilities of Fe, Mn or Cu/Zn-SODs.
Cu/Zn-SOD is competitively inhibited by N3- , CN-,102 and
by F-.103
SOD is found in our skin and it is essential in order for our
body to generate adequate amounts of skin-building cells
called fibroblasts. Among the common natural sources of
SOD are cabbage, Brussels sprouts, wheat grass, barley
grass and broccoli.
Catalase (CAT) is an enzyme responsible for the
degradation of hydrogen peroxide. It is a protective enzyme
present in nearly all animal cells. The functions of Human
erythrocyte catalase include catalyzing the decomposition of
H2O2 to water and oxygen. It is a tetramer of 4 polypeptide
chains. As with the chemical antioxidants, cells are
protected against oxidative stress by an interacting network
of antioxidant enzymes.104
Glutathione peroxidase (GPx) is an enzyme that is
responsible for protecting cells from damage due to free
radicals like hydrogen and lipid peroxides. The GPx
contains a single selenocysteine (Sec) residue in each of the
four identical subunits, which is essential for enzyme
activity.105 There are five GPx isoenzymes found in
mammals. The function of glutathione peroxidase, therefore,
is to reduce lipid hydroperoxides to their corresponding
alcohols and to reduce free H2O2 to water. Levels of GPx in
the body are closely linked with that of glutathione, the
master antioxidant. Glutathione (GSH for short) is a
tripeptide that not only protects the cells against ill effects of
pollution; it is also acts as the body’s immune system
boosters. It is present in high concentrations in the cells and
plays a pivotal role in maintaining them in reduced state lest
they suffer damage by oxidation by free radicals.
Combination of certain antioxidants like glutathione,
vitamin C and E, selenium and glutathione peroxidase are
very powerful in helping the body fight against the free
radicals. GSH ensures that the red blood cells remain intact
and protect the white blood cells (which are responsible for
immunity). Glutathione is found in vegetables and fruit, but
cooking will significantly reduce its potency. Taking it as a
supplement is a good idea.
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371
Glutathione-S-transferase (GST) is a family of enzymes
comprising a list of cytosolic, mitochondrial and
microsomal proteins which are capable of multiple reactions
with multitude of substrates, both endogenous or xenobiotic.
GSTs contribute to the phase II biotransformation of
xenobiotics by conjugating these compounds with reduced
glutathione to facilitate dissolution in aqueous cellular and
extra cellular media and from there, out of the body. GSTs
catalyse conjugation of reduced glutathione via the
sulfhydryl group, to electrophilic centers on a wide variety
of substrates. This activity is useful in the detoxification of
endogenous compounds such as peroxidised lipids as well as
metabolism of xenobiotics.
Glutathione reductase (GR) plays an indirect but
essential role in the prevention of oxidative damage within
the cell by helping to maintain appropriate levels of
intracellular glutathione (GSH). GSH, in conjunction with
the enzyme glutathione peroxidase (GP), is the acting
reductant responsible for minimizing harmful hydrogen
peroxide cellular levels. The regeneration of GSH is
catalyzed by GR. GR catalyzes the reduction of oxidized
glutathione (GSSG) to reduced glutathione, using β-
nicotinamide dinucleotide phosphate (NADPH) as the
hydrogen donor. Molecules such as NADPH act as hydride
donors in a variety of enzymatic processes. NADPH has
been suggested to also act as an indirectly operating
antioxidant, given its role in the re-reduction of GSSG to
GSH and thus maintaining the antioxidative power of
glutathione.
Chemical pathways of natural antioxidants
After absorption, all antioxidants undergo certain
chemical reactions in order to protect other compounds from
oxidation. Most natural antioxidants have areas of high
electron density within themselves in order to prevent other
molecules from remaining as radicals for extended periods
of time.
Natural antioxidants donate electrons from two major
electron‐rich sources: hydroxyl groups and double bonds.
After donating electrons, natural antioxidants undergo
additional chemical reactions in order to facilitate their
breakdown. The first major method that several antioxidants
use in order to prevent oxidation in other compounds is to
donate electrons from their hydroxyl (‐OH) groups.106
Sources of natural antioxidants
Various antioxidants are supplied to human body
through diet, both vegetarian as well as non-vegetarian.
Vitamins C and E, β-carotene and coenzyme Q are the most
common antioxidants of diet, out of which, Vitamin E is
present in vegetable oils and found abundantly in wheat
germ. It is fat soluble vitamin, absorbed in the gut and
carried in the plasma bylipoproteins. Out if 8 natural state
isomeric forms of vitamin E, α-tocopherol is the most
common and potent isomeric form. Being lipid soluble,
vitamin E can effectively prevent lipid peroxidation of
plasma membrane.107-108
Plants (fruits, vegetables, medicinal herbs) may contain
awide variety of free radical scavenging molecules such as
phenolic compounds (phenolic acids, flavonoids, quinones,
coumarins, lignans, stilbenes, tannins etc.), nitrogen
compounds (alkaloids, amines, betalains etc.), vitamins,
terpenoids (including carotenoids) and some other
endogenous metabolites which are rich in antioxidant
activity.109-112
Synthetic antioxidants
Synthetic antioxidants are chemically synthesized
compounds since they do not occur in nature and are added
to food as preservatives to help prevent lipid oxidation. Due
to the inherent instability of natural antioxidants, several
synthetic antioxidants have been used to stabilize fats and
oils. Butylated hydroxytoluene (BHT) and butylated
hydroxyanisole (BHA) were originally developed to protect
petroleum from oxidative gumming.113 However, these
compounds have been used as antioxidants in human foods
since 1954 and are perhaps the most common antioxidants
used in those foods today.114 BHT and BHA not only have
similar names, but similar structures and antioxidant activity
and are often used together in fats and oils. Despite the fact
that both BHT and BHA are included in the list of
substances that are "generally accepted as safe". Certain
chronic toxicity studies have implicated BHT as potential
tumor promoter when fed at high levels.115-116 In contrast,
BHA and BHT, may both be important inhibitors of
carcinogenesis, probably by way of their antioxidant
function.117 Thus, there have been some attempts to remove
these antioxidants, TBHQ (tert-butylhydroxyquinone) is
another synthetic antioxidant which is widely used in the
feed industry. Like BHT and BHA, TBHQ has a benzene
ring or phenol structure. Other examples of synthetic
antioxidants are propyl gallate (PG), dodecyl gallate (DG),
octylgallate (OG) and ethylene diaminetetraacetic acid
(EDTA).
Figure 2. Structures of some synthetic antioxidant
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372
Methods for assessing in vitro antioxidant activity
Due to the increasing interest in these biological
molecules for consumers, food scientists and the medical
fraternity, a quick and easy method for determining
antioxidant capacity would be most useful. The most
promising methods used to evaluate antioxidant properties
were summarized by Krishnaiah et al.118
Uses of antioxidants in technology
Epidemiological studies have been reported that many of
antioxidant compounds possess anti-inflammatory,
antiatherosclerotic, antitumor, antimutagenic,
anticarcinogenic, antibacterial and antiviral activities to
greater or lesser extent.119
In many cases, increased oxidative stress is a widely
associated in the development and progression of diabetes
and its complications which are usually accompanied by
increased production of free radicals or failure of
antioxidant defense.120 Though the intake of natural
antioxidants has been reported to reduce risk of cancer,
cardiovascular diseases, diabetes and other diseases
associated with aging, there is considerable controversy in
this area.121
Leukocytes and other phagocyte destroy bacteria,
parasites and virus-infected cells with NO, O2, H2O2, and
OCl-, which are powerful oxidants and protect humans from
infection. However, they also cause oxidative damage and
mutation to DNA and participate in the carcinogenic process
if remain unchecked.
It has been reported that antioxidants modulate the
pathophysiology of chronic inflammation up to some
extent.122 Moreover, experiments and studies infer that
antioxidants are needed to scavenge and prevent the
formation of ROS and RNS, out of them, some are free
radicals while some are not.123 There is growing evidence
that oxidative damage to sperm DNA is increased when
there is vitamin C insufficiency in diet.10 This strongly
suggests the protective role of antioxidant in our daily
diet.124
The antioxidants control gene behaviour and prevent
diseases. The antioxidant network is body's built-in
intelligence. It constantly monitors the health of each of the
trillions of cells in your body. Whenever a problem is
detected, antioxidants will turn on the appropriate gene,
which, in turn, activates the cells that it needs to solve the
problem. For example, antioxidants direct genes to alert the
immune system when there are invading viruses are detected.
The immune system then creates more white blood cells to
kill the viruses. But the process begins with the antioxidant
network. Because antioxidants can help regulate dangerous
genes, it opens up the possibility to treat diseases at their
root cause, by suppressing bad genes before they can do
harm, using antioxidants-the ultimate preventive medicine.
Food Preservatives
Antioxidants are used as food additives to help guard
against food deterioration.125 Consequently, packaging of
fresh fruits and vegetables contains an ~8% oxygen
atmosphere milk and milk products like cheese; meat, fish
and their products; spices and other dry foods like sugar,
honey, beverages, and chewing gum.126 Besides the direct
addition to food items, the antioxidants can be used to
preserve food by preventing the degradation of food
packaging during processing and storage. Thus, antioxidants
can be added to packaging materials like paper,
polyethylene, plastic and paperboard preventing the
oxidation of the material itself, or allowing the added
antioxidants to migrate into the packaged food inside and
prevent oxidation there.127-128
Antioxidants are an especially important class of
preservatives.129 These preservatives include natural
antioxidants such as ascorbic acid and tocopherols as well as
synthetic antioxidants such as, t-butylhydroquinone, BHA
and BHT.130-132 Antioxidant preservatives are also added to
fat-based cosmetics such as lipstick and moisturizers to
prevent rancidity.
Industrial uses
Antioxidants are frequently added to industrial products.
They are widely used to prevent the oxidative degradation of
polymers such as rubbers, plastics and adhesives that causes
a loss of strength and flexibility in these materials. Polymers
containing double bonds in their main chains, such as
natural rubber are especially susceptible to oxidation and
ozonolysis. Oxidation and UV degradation are also
frequently linked, mainly because UV radiation creates free
radicals by bond breakage. The free radicals then react with
oxygen to produce peroxy radicals which cause yet further
damage, often in a chain reaction.
Health benefits and risks
Due to the power of natural antioxidants to prevent the
generation of free radicals, it has been found that they are
particularly useful in preventing certain diseases. However,
though it is apparent that natural antioxidants have many
positive effects on health, it should also be taken into
consideration that they could also have harmful effects if
taken in excess.
Conclusions
In foods that may undergo oxidation, antioxidants,
function as an inhibitor of oxidation reactions through
various mechanisms. Nevertheless, some foods are deficient
in natural antioxidants and can easily deteriorate during
processing or in storage, necessitating the use of synthetic
antioxidants. However, most synthetic antioxidants are
effective at low concentrations, and the addition of higher
levels may lead to a pro-oxidant effect. Additionally, large
doses of synthetic antioxidants have been reported to impart
safety problems.
Natural and synthetic antioxidants Section C-Review
Eur. Chem. Bull. 2017, 6(8), 365-375 DOI: 10.17628/ecb.2017.6.365-375
373
Therefore, caution must be taken when selecting and
adding antioxidants in food systems. Meanwhile, the safety
of natural antioxidants should not be taken for granted as
antioxidants from natural sources are attracting more and
more attention.
The best way to get a variety of antioxidants in the diet is
to eat foods that represent all the colours of the rainbow.
Each color provides its own unique antioxidant effects.
Bright orange, deep yellow fruits and vegetables like carrots,
sweet potatoes, and apricots provide one type of antioxidant.
Red foods like tomatoes provide another. Green vegetables,
such as broccoli and cabbage, and blue or purple foods, like
blueberries, each have their own antioxidant packages.
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Received: 29.06.2017.
Accepted: 21.08.2017.
