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American Journal of Bioscience and Bioengineering
2014; 2(5): 60-71
Published online December 02, 2014 (http://www.sciencepublishinggroup.com/j/bio)
doi: 10.11648/j.bio.20140205.11
ISSN: 2328-5885 (Print); ISSN: 2328-5893 (Online)

Review article: Oxidative stress versus antioxidants

Said M. Al-Dalaen1, Aiman I. Al-Qtaitat2
1
Department of Pharmacology, Faculty of Medicine, Mu’tah University, Karak, Jordan
2
Department of Anatomy & Histology, Faculty of Medicine, Mu’tah University, Karak, Jordan

Email address:
[email protected] (S. M. Al-Dalaen), [email protected] (A. I. Al-Qtaitat)

To cite this article:

Said M. Al-Dalaen, Aiman I. Al-Qtaitat. Review Article: Oxidative Stress Versus Antioxidants. American Journal of Bioscience and
Bioengineering. Vol. 2, No. 5, 2014, pp. 60-71. doi: 10.11648/j.bio.20140205.11

Abstract: Oxidative stress is a phenomenon that reflects an imbalance between the production of reactive oxygen species
and so-called oxidants, and their elimination by protective mechanisms. These are referred to as antioxidative systems which
can detoxify the reactive intermediates, or repair the resulting damage causing toxic effects through the production of
peroxides and free radicals that damage all cell components. Further, some reactive oxidative species act as cellular messengers
in redox signaling that can cause disruptions in normal cellular signaling mechanisms. In humans, oxidative stress is thought to
be involved in the development of atherosclerosis, neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease,
cancer, diabetes mellitus, inflammatory diseases, as well as psychological diseases or aging processes. It is presently accepted
that the reactive oxygen species can be beneficial. Depending on the type of oxidants, intensity and time of redox imbalance, as
well as on the type of cells, oxidative stress can play a role in the regulation of other important processes. This is achieved
through modulation of signal pathways, influencing synthesis of antioxidant enzymes, repair processes, inflammation, or via
the immune system, as a way to attack and kill pathogens. This limits the potential for apoptosis and cell proliferation, and thus
affects malignant processes. Imprudent administration of antioxidants may therefore have a negative impact on the organism.

Keywords: Reactive Oxygen Species, Antioxidants, Oxidative Stress, Redox Stress, Signaling

Table 1. Nomenclature of the various O2 forms [12].

1. Summary
.
Triplet Oxygen (Ground state) O-O.
Reactive oxygen species (ROS) are chemically reactive Singlet Oxygen O-O:
molecules produced by living organisms as a result of normal Superoxide .
O-O:
.
cellular metabolism. At low to moderate concentrations, they Perhydroxyl radical O-O:H
function in physiological cell processes. However, when Hydrogen peroxide H:O-O:H
Hydrogen radical H: O.
present in high concentrations, they produce adverse Hydrogen ion H: O:
modifications to cell components, such as lipids, proteins, Water H:O:H
and DNA [1-3]. The shift in the oxidant/antioxidant balance
in favor of oxidants is termed “oxidative stress.” Oxidative
stress contributes to many pathological conditions, including
cancer, neurological disorders [4] atherosclerosis,
hypertension, ischemia/perfusion [5] diabetes, acute
respiratory distress syndrome, idiopathic pulmonary fibrosis,
chronic obstructive pulmonary disease [6] and asthma [7-10].
Aerobic organisms have integrated antioxidant systems,
which include enzymatic and nonenzymatic antioxidants that
are usually effective in blocking harmful effects of ROS.
However, in pathological conditions, the antioxidant systems
can be overcomed [11].

Figure 1. The activation states of oxygen [12].

61 Said M. Al-Dalaen and Aiman I. Al-Qtaitat: Review Article: Oxidative Stress Versus Antioxidants

2. Oxidants protein along the chain having a greater reduction potential

than the previous one. The final destination for an electron
2.1. Endogenous Sources of Oxidants along this chain is an oxygen molecule. In normal conditions,
ROS (shown in Figure 1 and table 1) are produced from oxygen is reduced to produce water. However, in about 1–3%
the activation of molecular oxygen, intracellularly through [11] of electrons passing through the chain, oxygen is
multiple mechanisms, as a result of normal cellular prematurely and incompletely reduced, resulting in the
metabolism. Their major sources are mitochondria, superoxide radical (·O2-). While superoxide is not
peroxisomes, endoplasmic reticulum, and the NADPH particularly reactive, it can inactivate specific enzymes or
oxidase (NOX) complex in cell membranes (Figure 2) [13, initiate lipids peroxidation in its protonated form,
14]. ROS can be classified as either free radicals or hydroperoxyl HO2· [15], O2- itself can also react with H2O2
nonradicals. and generate OH- [16]. Hydroxyl radical is the most reactive
Molecules containing one or more unpaired electrons and ROS and can damage proteins, lipids, carbohydrates and
thus giving reactivity to the molecule are called free radicals. DNA. It can also initiate lipid peroxidation by taking an
When two free radicals share their unpaired electrons, electron from polyunsaturated fatty acids. Hydrogen peroxide
nonradical forms are created. The three major ROS that are is also produced by xanthine oxidase, amino acid oxidase,
of physiological significance are superoxide anion (O2-.), and NADPH oxidase [17] and in peroxisomes by
hydroxyl radical (.OH), and hydrogen peroxide (H2O2) [11]. consumption of molecular oxygen in metabolic reactions. In
Mitochondria convert energy into ATP—a form that can be a succession of reactions, called Haber–Weiss and Fenton
utilized by the cell. The ATP production process, known as reactions (Figure 3), H2O2 can break down to OH- in the
oxidative phosphorylation, involves the transport of protons presence of transmission metals, such as Fe2+ or Cu2+ [18].
(hydrogen ions) across the inner mitochondrial membrane by Fe3 + + .O2 → Fe2++ O2 Haber-Weiss
means of the electron transport chain. In the electron
transport chain, electrons are passed through a series of Fe2+ + H2O2→ Fe3 + + OH- + .OH Fenton reaction
proteins via oxidation-reduction reactions, with each acceptor

Figure 2. Different ROS sources [13].

 American Journal of Bioscience and Bioengineering 2014; 2(5): 60-71 62

Figure 3. Fenton reaction [18].

Granulocytic enzymes further expand the reactivity of mercury, nickel, lead, and arsenic—can induce generation of
H2O2 via eosinophil peroxidase and myeloperoxidase (MPO). reactive radicals. This can cause cellular damage via
In activated neutrophils, H2O2 is consumed by MPO. In the depletion of enzyme activities through lipid peroxidation and
presence of chloride ion, H2O2 is converted to hypochlorous reaction with nuclear proteins and DNA, where ROS
acid (HOCl), which is highly oxidative and plays an generated by metal-catalyzed reactions can modify DNA
important role in killing of the pathogens in the airways [19]. bases. Three base substitutions, G → C, G → T, and C → T,
However, HOCl can also react with DNA, induce DNA– can occur as a result of oxidative damage by metal ions, such
protein interactions, produce pyrimidine oxidation products as Fe2+, Cu2+, and Ni2+. Previous studies have shown that G
and add chloride to DNA bases [20]. Eosinophil peroxidase → C can be predominantly produced by Fe2+, while C → T
and MPO also contribute to the oxidative stress through substitution is typically achieved by Cu2+ and Ni2+ [30].
modification of proteins by halogenations, nitration, and In the presence of O2, ionizing radiation converts hydroxyl
protein cross-links via tyrosyl radicals [21]. radical, superoxide, and organic radicals to hydrogen
The peroxyl radicals (ROO..) are another type of oxygen- peroxide and organic hydroperoxide, which can react with
derived free radicals, the simplest of which is hydroperoxyl redox active metal ions, such as Fe and Cu, via Fenton
radical (ROO..) that plays a role in fatty acid peroxidation. reactions, and thus induce oxidative stress [31]. In addition, it
Free radicals can trigger lipid peroxidation chain reactions by can generate damaging intermediates through interaction
abstracting a hydrogen atom from a side chain methylene with water, a process termed radiolysis. Since water
carbon. The lipid radical then reacts with oxygen to produce comprises 55-60% of the human body, the probability of
peroxyl radical. Peroxyl radical initiates a chain reaction and radiolysis is quite high under the presence of ionizing
transforms polyunsaturated fatty acids into lipid radiation. The outcome is conversion of water into hydroxyl
hydroperoxides, which are very unstable and easily radical (-OH), hydrogen peroxide (H2O2), superoxide radical
decompose to secondary products, such as aldehydes and (O2-) and ultimately oxygen (O2) [32]. Moreover, according
malondialdehydes. Isoprostanes are another group of lipid to the findings of extant studies, various signal transduction
peroxidation products that are generated via the peroxidation molecules—such as extracellular signal-regulated kinase 1
of arachidonic acid and have also been found to be elevated and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38—
in plasma and breath condensates of asthmatics [22]. and transcription factors—such as activator protein-1 (AP-1),
nuclear factor-κB (NF-κB), and p53—are activated under
2.2. Exogenous Sources of Oxidants effect of ionizing radiation. This results in the expression of
Exogenous ROS can be produced as a result of smoking radiation response-related genes [33, 34].
[23] as well as exposure to pollutants, ozone [24], hyperoxia
[25], heavy metals [26] or radiation [27]. Cigarette smoke 3. Oxidative Stress-Induced Cellular
contains many oxidants, free radicals and organic compounds,
such as superoxide and nitric oxide [24]. Ozone exposure can Damage
cause lipid peroxidation and induce influx of neutrophils into The targets of ROS damage include all major biomolecular
the airway epithelium. groups, as discussed below.
Short-term exposure to ozone also causes the release of
inflammatory mediators, such as MPO, eosinophil cationic 3.1. Proteins
proteins, lactate dehydrogenase and albumin [28].
Hyperoxia refers to conditions characterized by oxygen It is well known that ROS can target almost all cellular
levels that are higher than normal partial pressure of oxygen compounds. According to the findings of several studies,
in the lungs or other body tissues. This leads to greater ROS can react with several amino acid residues in vitro,
production of reactive oxygen and nitrogen species [29]. generating a wide range of products—from modified and less
Heavy metal ions—such as iron, copper, cadmium, active enzymes to denatured, non-functioning proteins [35].
63 Said M. Al-Dalaen and Aiman I. Al-Qtaitat: Review Article: Oxidative Stress Versus Antioxidants

Fragmentation of the peptide chain and aggregation of mechanisms destroy most of these and any damage to the
cross-linked reaction products result in an altered electrical cells is constantly repaired. However, under the severe levels
charge and increased susceptibility to proteolysis by of oxidative stress that cause necrosis, the damage causes
degradation by specific proteases. Here, the amino acids in a ATP depletion, preventing the control of cell death by
peptide differ in their susceptibility to attack, while the apoptosis and causing cell disintegration [50].
various forms of activated oxygen differ in their potential
reactivity [36].
Cysteine and methionine residues in proteins are 4. Effects of Oxidative Stress on Signal
particularly susceptible to oxidation [37]. For example, Transduction
oxidation of sulfhydryl groups or methionine residues of
proteins causes conformational changes, protein unfolding, Oxidative stress can cause disruption of the GSH/GSSG
and degradation [38, 39]. Enzymes that have metals at or ratio, leading to activation of redox sensitive transcription
close to their active sites are especially more sensitive to factors, such as the nuclear factor of activated T cells (NF-κB)
metal catalyzed oxidation, which can inhibit their activities and hypoxia-inducible factor 1 (AP-1). Owing to their
[40]. involvement in inflammatory responses, these factors can
facilitate the transmission of information into the cell.
3.2. Lipids Tyrosine kinase receptors, most of the growth factor
receptors—such as epidermal growth factor receptor,
Oxidative stress can induce lipid peroxidation, causing vascular endothelial growth factor receptor, and receptor for
different arrangement in the membrane lipid bilayer. This platelet-derived growth factor—as well as protein tyrosine
results in inactivation of the membrane-bound receptors and phosphatases and serine/threonine kinases are targets of ROS
enzymes and causes an increase in tissue permeability [41]. [51]. Moreover, oxidants can regulate many of the
Products of lipid peroxidation, such as malodialdehyde and extracellular signal regulated kinases, such as p38, which are
unsaturated aldehydes, are capable of inactivating many the members of mitogen-activated protein kinase family. As
cellular proteins by forming protein cross-linkages [42]. This such, they are involved in several processes in the cell,
causes depletion of intracellular GSH, induces peroxide including proliferation, differentiation, and apoptosis. ROS
production [43] activates epidermal growth factor receptor can activate NF-κB by phosphorylating IκBs at serine
[44] and induces fibronectin production [45]. residues, which frees NF-κB to enter the nucleus to activate
3.3. DNA gene transcription [52]. A number of kinases have been
reported to phosphorylate IκBs; these kinases are targets for
Most of the long-term effects of oxidative stress are oxidative signals to activate NF-κB [53]. As a result of NF-
inflicted by modifications of DNA [46] which involves κB activation via oxidation, several antioxidant defense-
degradation of bases, single- or double-stranded DNA breaks, related genes that can participate in immune response are
purine, pyrimidine or sugar-bound modifications, mutations, activated. These include IL-1b, IL-6, tumor necrosis factor-α,
deletions or translocations, and cross-linking with proteins. IL-8, and several adhesion molecules. NF-κB also regulates
Most of these DNA modifications are highly relevant to angiogenesis, proliferation and cell differentiation [54].
carcinogenesis, aging, and neurodegenerative, cardiovascular,
and autoimmune diseases. DNA damage similar to that 5. Oxidative Stress and Diseases
induced by oxidative stress can also be induced by ionizing
radiation. Promoter regions of genes contain transcription 5.1. Aging
factor-binding sites that have consensus sequences. These
contain GC-rich sequences are susceptible for oxidant attacks, In an attempt to explain the aging process, many theories
which can change the expression of the related gene [47]. have been put forward [55, 56]. However, only the “free
Single-base damage by radiation or oxidation, such as 8- radical theory of aging” [57] has gained universal acceptance,
oxoguanine and thymine glycol, is well known. However, the as it is supported by the fact that the production of free
research focus has recently shifted to some of the more radicals and the free radical damage increases with age [58].
complex lesions, such as tandem DNA lesions, formed at This theory postulates that free radicals in the body cause
substantial frequency by ionizing radiation and metal- oxidative damage to cellular components—a process that
catalyzed H2O2 reactions. results in altered cellular function, compromised tissue and
Under anoxic conditions, the predominant double-base organ function, ultimately leading to death. The free radial
lesion is a species in which C8 of guanine is linked to the 5- theory is also supported by the “rate of living” hypothesis,
methyl group of an adjacent 3'-thymine (G [8, 5- Me] T) [48]. which inversely links metabolic rate with the longevity of the
Most of these oxygen-derived species are produced at a low organisms [59]. This is supported by empirical evidence
level by normal aerobic metabolism. As a result of oxidation, proved by indicating that oxidative damage to proteins, DNA
5-methyl cytosine is converted into 5-hydroxy methyl uracil, and lipids increases with age [58]. As free radical-mediated
due to a deamination/oxidation reaction, affecting DNA oxidative stress increases with age, it may overwhelm the
organization and repair activity [49]. Normal cellular defense natural repair systems in the elderly [60]. Thus, it is a major
contributor to diseases associated with aging [61].
 American Journal of Bioscience and Bioengineering 2014; 2(5): 60-71 64

5.2. Cardiovascular Disease neurodegenerative diseases [74] which are characterized by

loss of specific neuronal populations. This is often
Vascular proliferation and inflammation are closely linked accompanied by intraneuronal damage, as well as
[62] and excessive proliferation of vascular cells plays an extracellular accumulation of fibrillary materials.
important role in the pathology of vascular occlusive disease.
Free radicals are considered to play a causal role in this 5.6. Parkinson’s Disease
process [63]. ROS lead to the oxidation of low density
lipoprotein, which accumulates within plaques. It thus This progressive neurodegenerative movement disorder is
contributes to the inflammatory state of atherosclerosis and considered the most common form of motor system
plays a key role in its pathogenesis [64]. Oxidized-LDL leads degeneration, affecting approximately 1% of the population
to endothelial dysfunction, and can result in either cell over the age of 65 [75]. Empirical evidence suggests the
growth or apoptotic cell death, causing vasoconstriction. Free involvement of free radicals in the pathogenesis of this
radicals have also been implicated in congestive heart failure disease. It has been observed that that oxidation of dopamine
[65]. yields potentially toxic semiquinones. Moreover, the
accelerated metabolism of dopamine by monoamine-oxidase-
5.3. Diabetes B may induce an excessive formation of hydrogen peroxide,
superoxide anions, and hydroxyl radicals, which not only
Findings of pertinent studies indicate that free radical- maintain the oxidative stress level, but also initiate/propagate
induced damage also plays a role in the development of apoptosis of the dopaminergic neurons [76]. According to the
insulin resistance, β-cell dysfunction, impaired glucose reports in the pertinent literature, Parkinson's disease is
tolerance, and type II diabetes mellitus [66]. Hyperglycemia associated with increased oxidative damage to DNA [77],
can induce oxidative stress through several mechanisms, proteins [78] and lipids [79].
including glucose autoxidation, the formation of advanced
glycation end-products (AGEs), and activation of the polyol 5.7. Huntington’s Disease
pathway [67]. In diabetics, a significant increase in protein
glycation (AGE) has been noted. Moreover, evidence This inherited autosomal dominant neurodegenerative
suggests that, owing to their accumulation, prevalence of disease is characterized by uncontrollable movements,
microvascular lesions increases. These are present in diabetic irritability and depression [80]. There is a direct evidence to
retinopathy, and are also responsible for cardiovascular support the involvement of free radicals in the pathogenesis
complications in diabetic patients [67, 68]. The damage of Huntington’s disease, in that increased levels of F2-
caused by ROS has also been implicated in primary open isoprostanes have been detected in the cerebrospinal fluid of
angle glaucoma (POGA), which is the leading cause of the patients compared to those measured in the healthy
irreversible blindness [69]. persons [81].

5.4. Cancer 5.8. Alzheimer’s Disease

ROS can activate the initiation, promotion and progression This neurodegenerative disorder is characterized by
stages of carcinogenesis [70] due to the interaction between cognitive impairment and a gradual loss of memory,
free radicals and DNA components. By damaging its bases language skills, and dementia. It eventually leads to death
and the deoxyribose backbone, it causes mutations in crucial due to the loss of neurons and synapses [82]. Oxidative
genes, thus leading to cancer [71]. In support of this free damage may play a role in amyloid deposition in Alzheimer’s
radical-mediated damage to DNA, either through arrest or disease, and oxidizing conditions can cause protein cross-
induction of transcription, induction of signal transduction linking and aggregation of β-amyloid protein, tau and other
pathways, replication errors, and genomic instability occurs. cytoskeletal proteins [83]. The accumulated β-amyloid can
All these phenomena are associated with carcinogenesis [49] cause oxidation of the nonsaturated carbohydrate side chains
which has been found in various cancer tissues. Moreover, of membrane lipids, which leads to the disintegration of the
there is a direct link between the size of benign tumors and neural membrane. The outcome of this process is cell lysis
the amount of DNA oxidized product, 8-hydroxyguanine (8- due to lipid peroxidation [84] which is associated with DNA
OH-G) adduct formation. Understanding this process may be damage and oxidative modification of proteins in the frontal
important in explaining the transformation of benign to cortex of brain affected by Alzheimer’s disease [85].
malignant tumors [72]. In cancer cells, the high level of 5.9. Stroke
oxidative stress can induce apoptosis or even necrosis, while,
its low level can stimulate cell division and thus promote In the patients that have suffered stroke, neuronal death is
tumor growth [73]. caused by the free radicals arising from various sources, such
as xanthine oxidase, cyclooxygenase, inflammatory cells and
5.5. Neurodegenerative Diseases mitochondria [86]. The mitochondrial electron transport
A growing body of evidence indicates that free radicals are chain is altered during ischemia and reperfusion and is also a
involved in the initiation of cellular injury observed in likely source of free radicals. This can result in increased
formation of superoxide radical anions [87].
65 Said M. Al-Dalaen and Aiman I. Al-Qtaitat: Review Article: Oxidative Stress Versus Antioxidants

The accumulation of blood borne inflammatory cells, such of oxidants before these attacks the cells (Figure 4). There are
as neutrophils and monocytes/macrophages, which can occur highly complex antioxidant systems (enzymatic and
during reperfusion, can also promote further oxidative stress. nonenzymatic) in human cells, working in collaboration in
This can cause lipid peroxidation and oxidative damage to other to protect the body against free radical damage.
DNA in ischemic stroke patients [88]. In addition; increased Antioxidants can be endogenous or obtained exogenously,
ROS levels can make the brain more susceptible to oxidative as a part of a diet or through dietary supplements. They can
stress due to a variety of reasons. For example, the brain also be consumed as compounds that do not neutralize free
could consume a significant amount of the body’s oxygen radicals, but rather enhance endogenous activity.
supply, or have a relatively poor antioxidant defense system. An ideal antioxidant should be readily absorbed, quench
Alternatively, it could be enriched in pro-oxidant molecules free radicals, and chelate redox metals. It should also work in
or contain high concentration of readily peroxidizable lipids both aqueous and/or membrane domains, positively affecting
[89]. gene expression.
Endogenous antioxidants play a crucial role in maintaining
6. Antioxidants optimal cellular functions. However, under conditions that
promote oxidative stress, endogenous antioxidants may not
Humans have evolved complex antioxidants strategies be sufficient. In such cases, dietary antioxidants should be
against prooxidant conditions. The antioxidant defensive supplied to maintain optimal cellular functions. Some
system has many components, and a deficiency of any of antioxidants can interact with other antioxidants,
these components can cause destruction in the overall regenerating their original properties. This process is referred
antioxidant status of an individual [90]. Antioxidants are the to as the “antioxidant network.” [91].
molecules that have the ability to counterbalance the effects

Figure 4. Mutual association between oxidants and antioxidants [92].

6.1. Enzymatic Antioxidants areas containing high amounts of type I collagen fibers and
around pulmonary and systemic vessels. It has also been
The major enzymatic antioxidants found in the lungs are detected in the bronchial epithelium, alveolar epithelium, and
superoxide dismutases (SODs) (EC 1.15.1.11), catalase (EC alveolar macrophages [95]. Overall, CuZn-SOD and Mn-
1.11.1.6), glutathione peroxidases (GSH-Pxs) (EC 1.11.1.9) SOD are generally thought to act as bulk scavengers of
and glutathione-S-transferase (GSTs) (EC 2.5.1.18) [93]. In superoxide radicals. The relatively high EC-SOD level in the
addition to these major enzymes, other antioxidants, lung with its specific binding to the extracellular matrix
including heme oxygenase-1 (EC 1.14.99.3), and redox components may represent a fundamental component of lung
proteins, such as thioredoxins (TRXs, EC 1.8.4.10), matrix protection [96].
peroxiredoxins (PRXs, EC 1.11.1.15), and glutaredoxins, Cu, Zn-SOD has two identical subunits, with a molecular
have been found to play crucial roles in the pulmonary weight of 32 kDa. Each subunit contains a dinulcear metal
antioxidant defenses. cluster, comprising of copper and zinc ions as the active site,
Since superoxide is the primary ROS produced in a variety and it specifically catalyzes the dismutation of the superoxide
of sources, its dismutation by SOD is of primary importance anion to oxygen and water [97]. The mitochondrial Mn-SOD
for each cell. All three forms of SOD—CuZn-SOD, Mn-SOD, is a homotetramer with a molecular weight of 96 kDa and
and EC-SOD—are widely expressed in human tissues [94]. contains one manganese atom per subunit. It vacillates from
Mn-SOD is localized in the mitochondria matrix. EC-SOD is Mn (III) to Mn (II) and back to Mn (III) during the two-step
primarily localized in the extracellular matrix, especially in
 American Journal of Bioscience and Bioengineering 2014; 2(5): 60-71 66

dismutation of superoxide [97]. Extra-cellular superoxide 6.2. Nonenzymatic Antioxidants

dismutase contains copper and zinc. It is a tetrameric
secretary glycoprotein, characterized by a high affinity for 6.2.1. Vitamin E (α-Tocopherol)
certain glycosaminoglycans, such as heparin and heparin This fat-soluble vitamin is considered a major powerful
sulphate. However, its regulation in mammalian tissues membrane-bound antioxidant, employed by the cell [111] as a
occurs primarily in a manner coordinated by cytokines, rather protection against lipid peroxidation [112]. During the
than as a response to oxidative stress [97]. antioxidant reaction, α-tocopherol is converted into α-
H2O2 produced by the action of SODs or oxidases, such as tocopherol radical by the donation of labile hydrogen to a
xanthine oxidase, is reduced to water by catalase and the lipid or lipid peroxyl radical. Thus, the α-tocopherol radical
GSH-Px. Catalase exists as a tetramer composed of four can be reduced to the original α-tocopherol form by ascorbic
identical monomers, each of which contains a heme group at acid [113].
the active site. Degradation of H2O2 is accomplished via the 6.2.2. Vitamin C (Ascorbic Acid)
conversion between two conformations of catalase- As it is water-soluble, Vitamin C acts in the aqueous
ferricatalase (iron coordinated to water) and compound I environments of the body, along with the antioxidant
(iron complexed with an oxygen atom). Catalase also binds enzymes. Vitamin C cooperates with Vitamin E to regenerate
NADPH as a reducing equivalent to prevent oxidative α-tocopherol from α-tocopherol radicals in membranes and
inactivation of the enzyme (formation of compound II) by lipoproteins [112] (Figure 5). By raising intracellular
H2O2 as it is reduced to water [98]. Catalase has one of the glutathione levels, it also plays an important role in protein
highest turnover rates of all enzymes; one molecule of thiol group protection against oxidation [114]. Yuanyuan et al.
catalase can convert approximately 6 million molecules of (2014) [115] reported that vitamin C decreased ROS and
hydrogen peroxide to water and oxygen each minute [97]. DNA damage of severe CAP PBMC in vitro, and vitamin C
The GSH-Pxs are a family of tetrameric enzymes that contain decreased TNF-α and IL-6 in whole blood cells from severe
the unique amino acid selenocysteine within the active sites CAP.
and use glutathione (GSH) to reduce H2O2 and lipid
peroxides to their corresponding alcohols. While four
GSHPxs have been described, encoded by different genes,
GSHPx-1 (cellular GSH-Px) is ubiquitous. It reduces H2O2
and fatty acid peroxides, but not esterified peroxyl lipids [99].
Esterified lipids are reduced by membrane-bound GSH-Px-4
using several different thiols as reducing equivalents. GSH-
Px-2 (gastrointestinal GSH-Px) is localized in gastrointestinal
epithelial cells, where it serves to reduce dietary peroxide
levels [100]. GSH-Px-3 (extracellular GSH-Px) is the only
member of the GSH-Px family that resides in the
extracellular compartment and is believed to be one of the
most important extracellular antioxidant enzymes in
mammals [101]. Figure 5. Ascorbic acid – antioxidant and potential prooxidant properties
[92].
GSTs can inactivate secondary metabolites, such as
unsaturated aldehydes and hydroperoxides. Presently, three 6.2.3. Carotenoids (β-Carotene)
major families of GSTs are recognized—cytosolic GST, These are mainly colored pigments present in plants and
mitochondrial GST [102, 103] and membrane-associated microorganisms. Epidemiological studies have revealed that
microsomal GST that plays a role in eicosanoid and GSH a diet rich in carotenoids is correlated with a lower risk of
metabolism [104]. During non-stressed conditions, Mu and age-related diseases [116]. Primarily, β-carotene has been
Pi classes of cytosolic GSTs can interact with kinases Ask1 found to react with peroxyl (ROO.) to prevent damage in
and JNK, respectively, resulting in their inhibition [105]. The lipophilic compartments [117] hydroxyl (.OH), and
dissociation of GSTP1 from JNK in response to oxidative superoxide (O2-.) radicals [118]. The antioxidant activity of
stress [106] results in the recovery of peroxiredoxin VI (PRX carotenoids arises due to their ability to delocalize unpaired
VI) enzyme activity through glutathionylation of the oxidized electrons, and thus quench singlet oxygen without
protein [107]. degradation [119]. The efficacy of carotenoids with respect to
The enzymatic antioxidants also include six different types physical quenching is related to the number of conjugated
of PRXs, each playing a major role in the protection of double bonds present in the molecule. Both β-Carotene and
alveolar epithelium, PRX VI in particular [108]. PRX V has retinoic acid are capable of regulating different transcription
been found to function as a peroxynitrite reductase [109]; factors [120], β-Carotene inhibits the oxidant-induced NF-κB
according to some authors, it may also function as a potential activation and interleukin (IL)-6 and tumor necrosis factor-α
protective compound in the development of ROS-mediated production. On the other hand, retinoic acid can affect cell
lung injury [110]. apoptosis, arrest cell cycle, or both [121, 122].
67 Said M. Al-Dalaen and Aiman I. Al-Qtaitat: Review Article: Oxidative Stress Versus Antioxidants

6.2.4. Thiol Antioxidants addition, a variety of environmental factors, such as air

Glutathione (GSH) is the major thiol-disulphide redox pollutants or cigarette smoke, can result in the production of
intracellular multifunctional soluble antioxidant of the cell. It ROS, which can also affect the expression of several genes
can be found abundant in cytosol, nuclei, and mitochondria by upregulation of redox-sensitive transcription factors and
[123]. It can be found in the reduced form, i.e., as GSH, or in chromatin remodeling through alteration in histone
the oxidized form, known as GSSG (glutathione disulphide). acetylation/deacetylation. The human body deals with the
The antioxidant capacity of thiol compounds is attributed to pathological effects of ROS by utilizing the endogenous
the presence of sulfur atom, which can easily accommodate the antioxidant enzymatic system and by the ingestion of
loss of a single electron [124]. As oxidized glutathione (GSSG) exogenous antioxidants in the diet. If the oxidative stress
is accumulated inside the cells, the GSH/GSSG ratio is a exceeds the protection afforded by antioxidants, the aging
reliable indicator of oxidative stress of an organism [125]. It process and some of the diseases associated with it—such as
can act as a co-factor for several detoxifying enzymes, cardiovascular diseases, neurodegenerative diseases, diabetes
participate in amino acid transport across plasma membrane, and cancer — can accelerate. Regulation of redox state is
scavenge hydroxyl radical and singlet oxygen directly, and critical for cell viability, activation, and proliferation, as well
regenerate Vitamin C and E back to their active forms [123]. In as organ function.
addition, evidence suggests that GSH protects cells against
apoptosis by interacting with proapoptotic and antiapoptotic
signaling pathways. It also regulates and activates several References
transcription factors, such as AP-1, NF-κB, and Sp-1 [123].
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