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Free radicals and human health

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International Journal of Innovation Sciences and Research
Available online at
Vol.4, No.6, pp.218-223, June- 2015
http://www.ijisr.com

REVIEW ARTICLE

FREE RADICALS AND HUMAN HEALTH

1, *Mustafa
Taha Mohammed, 2Sura Mohammed Kadhim, 1Abdulkadir Mohammed Noori
Jassimand and 1Sarah Isam Abbas
1Department of Chemistry, College of Science, Al-Mustansiriyah University,Baghdad, Iraq
2Ministry of Education, Rusafa-1, Baghdad, Iraq

Accepted 24th May, 2015; Published Online 30th June, 2015

ABSTRACT
In recent years, there has been a large quantity of attention toward the field of free radical chemistry. Free radicals react
reactive oxygen species
(ROS) and reactive nitrogen species(RNS) are generated by our body by different endogenous systems, exposure to various physiochemical
conditions or pathological states. A balance between free radicals and antioxidants is needful for proper physiological actio
action. If free radicals
overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues.
ensues. Free radicals consequently adversely change lipids,
proteins, and DNA and trigger a number of human diseases. Hence application of external source of antioxidants can assist in coping this
oxidative stress. Thus, the search for effective, nontoxic natural
natural compounds with antioxidative activity has been intensified in recent years. The
attendant review provides a brief overview on oxidative stress mediated cellular damages and role of dietary antioxidants as functional foods in
the management of human diseases.

Key Words: Free radicals, Oxidative stress, Antioxidant.

1- INTRODUCTION molecules, resultingin cellular damage. ROS are generated by

a number of pathways. Most of the oxidantsproduced by cells
A free radical can be defined as any molecular species capable occur as:
of independent existence that contains an unpaired electron in
an atomic orbital. The presence of an unpaired electron results  A consequence of normal aerobic metabolism:
in certain common properties that are shared by most radicals. approximately 90% of the oxygenutilized by the cell is
Many y radicals are unstable and highly reactive. They can consumed by the mitochondrial electron transport system.
either donate an electron to or accept an electron from other  Oxidative burst from phagocytes (white blood cells) as
molecules, therefore behaving as oxidants or reductants part of the mechanism by whichbacteria and viruses are
(Cheeseman, 1993). The most important oxygen-containing
oxygen killed, and by which foreign proteins (antigens) are
free radicals in many diseasee states are hydroxyl radical, denatured.
superoxide anion radical, hydrogen peroxide, oxygen singlet,  Xenobioticmetabolism,
ticmetabolism, i.e., detoxification of toxic
hypochlorite, nitric oxide radical, and peroxynitrite radical. substances.
These are highly reactive species, capable in the nucleus, and
in the membranes of cells of damaging biologically relevant
molecules such as DNA, proteins, carbohydrates, and lipids
(Young and Woodside, 2001). Free radicals attack important
macromolecules leading to cell damage and homeostatic
disruption. Targets of free radicals include all kinds of
molecules
cules in the body. Among them, lipids, nucleic acids, and
proteins are the major targets.
2- Reactive Oxygen Species
Reactive oxygen species (ROS) is a term that encompasses all
highly reactive, oxygencontaining molecules, including free
radicals. Types of ROS include the hydroxyl radical,the
superoxide anion radical, hydrogen peroxide, singlet oxygen,
nitric oxide radical,hypochlorite radical, and various lipid
peroxides. All are capable of reacting withmembrane lipids,
nucleic acids, proteins and enzymes, and other small
*Corresponding author:Mustafa
Mustafa Taha Mohammed
Department of Chemistry, College of Science, Al-Mustansiriyah
Al Figure 1. An overall picture of the metabolism of ROS and the
University, Baghdad, Iraq. mechanism of oxidative tissue damage leading to pathological
conditions
International Journal of Innovation Sciences and Research 219

Consequently, things like vigorous exercise, which accelerates Cyclooxygenase‐1 has been implicated in ROS production
cellular metabolism; chronicinflammation, infections, and through formation ofendoperoxides, which are susceptible to
there illnesses; exposure to allergens and the presence scavenging by some antioxidants in cells stimulated with
ofsyndrome; and exposure to drugs or toxins such as cigarette TNF‐α, interleukin‐1, bacterial lipopolysaccharide, or the
smoke, pollution,pesticides, and insecticides may all tumor promoter 4‐Otetradecanoylphorbol‐13‐acetate (Dröge,
contribute to an increase in the body’s oxidant load (Uday 2002).
Bandyopudyaet al., 1999; Chitra and Pillai, 2002)
3.2. Non‐regulated production of reactive oxygen species
3- Sources of reactive oxygen species and free radicals in
an organism 3.2.1. Mitochondrial respiration

All aerobic organisms produce ROS physiologically. The five The four‐electron reduction of oxygen occurs within the
most productive pathways are involved in regulating the mitochondrial electron transport system of all cells
production of ROS/RNS and the resulting effects on signalling undergoing aerobic respiration. It is estimated that 2‐3% of O2
cascades. The five mechanisms described produce ROS in a consumed by mitochondria is incompletely reduced, yielding
non‐regulated mode. However, there are many sources within ROS (Turrens, 2003) and 1‐5% leads to H2O2production.It is
the cells that are only mentioned. well documented that mitochondria are a source of H2O2;
however, the release of O2•‐ from mitochondria into the
3.1. Regulated production of reactive oxygen and nitrogen cytosol has yet to be definitively established (Molleret al.,
species 2007).
3.1.1. Nitric oxide synthase (NOS) 3.2.2. Chloroplasts
•
Nitric oxide (NO ) is produced from a guanidine nitrogen of The ability of phototrophs to convert light into biological
L‐arginine via electron transfer from NADPH in two energy is critical for life andtherefore organisms capable of
successive steps.The enzyme responsible this exists in three photosynthesis are especially at risk of oxidative damage,due
isoforms:neuronal (nNOS, type I, NOS‐I or NOS‐1), to their bioenergetic lifestyle and the abundance of
endothelial (eNOS, type III, NOS‐III or NOS‐3) and inducible photosenzitizers and oxidablepolyunsaturated fatty acids in
(iNOS, type II, NOS‐II or NOS‐2). nNOS and eNOS are the chloroplast envelope.
constitutively expressed, but their activity is regulated by the
intracellular Ca2+ concentration. nNOS exhibits 3.2.3. Xanthine oxidoreductase (XOR)
NADPH‐diaphorase (NADPH‐d) activity (Miller, 2004).
XOR exists as either an oxidase (XO) which transfers
3.1.2. NADPH oxidase reducing equivalents to oxygen, or as a dehydrogenase (XDH)
that utilizes NAD or oxygen as the final electron acceptor. The
3.1.2.1. NADPH oxidase in phagocytic cells enzyme is derived from xanthine dehydrogenase by
proteolytic cleavage. It contains molybdenum in the form of
Activated neutrophils and macrophages produce superoxide
molybdopterine, and two clusters with iron and sulfur
and its derivatives as cytotoxic agents forming part of the
compounds of FAD cofactor in both subunits. The enzyme
respiratory burst via the action of membrane bound NADPH
catalyzes the production of uric acid with co‐production of
oxidase on molecular oxygen.
O2•‐. The physiological substrates, xanthine and hypoxanthine,
3.1.2.2. NADPH oxidase in nonphagocytic cells bind with the oxidized enzyme and donate two electrons into
the molybdenum cofactor reducing it from Mo6+ to Mo4+.
Fibroblasts, endothelial cells, vascular smooth muscle cells, Substrates are hydroxylated by H2O at the molybdenum site as
cardiac monocytes and thyroid tissue nonphagocytic the electrons travel via two iron‐sulfide residues to flavine–
NAD(P)H oxidase (similar but not identical to phagocytic adenine dinucleotide (FAD) (Hazellet al., 1994; Berry and
NADPH oxidase) produce O2•‐ and to regulate intracellular Hare, 2004).
signalling cascades (Gieseet al., 2001; Zhaoet al., 2007). In
most of these, rac1 is involved in the induction of NAD(P)H 3.2.4. Dopamine (DA)
oxidase activity (Joneset al., 1996; Zweieret al., 1994).
As a neurotransmitter, DA is stable in the synaptic vesicle.
Muscle cells and fibroblasts account for the majority of O2•‐
When an excess of cytosolic DA exists outside of the synaptic
produced in the normal vessel wall. The NAD(P)H oxidase
vesicle, DA is easily metabolized via monoamino oxidase
isoforms of the cardiovascular system are
(MAO) or by autooxidation to produce ROS, subsequently
membrane‐associated enzyme that appear to utilize both
leading to the formation of neuromelanin . During the
NADH and NADPH (Gieseet al., 2001).
oxidation of DA by MAO, H2O2 and dihydroxyphenylacetic
3.1.3. Arachidonate cascade enzymes acid are generated (Gill and Tuteja, 2010). Spontaneously
oxidized cytosolic DA produces O2•‐ and reactive quinones
3.1.3.1. lipoxygenase (5‐LOX) such as DA quinones or DOPA quinones. DA quinones are
The enzyme 5‐LOX has been identified as an inducible source also generated in the enzymatic oxidation of DA by COX in
of ROS production inlymphocytes (Bonizziet al., 2000; the form of prostaglandin H synthase, LOX, tyrosinase and
McIntyreet al., 1999), but the evidence for its physiological XOR. These quinones are easily oxidized to the cyclized
role in redox signalling isstill scarce. aminochromes: Dachrome and DOPA‐chrome, and are then
finally polymerized to form melanin, as reviewed in
3.1.3.2. Cyclooxygenase (COX‐1) (Miyazaki and Asanuma, 2008). Although ROS from the
autooxidation of DA show widespread toxicity not only in DA
International Journal of Innovation Sciences and Research 220
neurons
urons but also in other regions, highly reactive DA quinone produce different free radicals. Thus, even a single cell can
or DOPA quinone exert cytotoxicity predominantly in DA produce many different kinds of free radicals.
neurons and surrounding neural cells. It is thought that DA
acts as an endogenous neurotoxin, contributing to the 4.3. Stress
pathology of neurodegenerative
ive disorders and The pressures common in industrial societies can trigger the
induced damage in the striatum (Xiaet al., 2001;
ischemia‐induced body's stress response to mass produce free radicals. The
Maragoset al., 2004). stress response races the body's ener energy-creating apparatus,
increasing the number of free radicals as a toxic by by-product.
3.2.5. Photosensitization reactions
Moreover, the hormones that mediate the stress reaction in the
Photosensitization reactions involve the oxidation of organic body - cortisol and catecholamine - themselves degenerate
compounds by atmosphericoxygen upon exposure to visible into particularly destructive free radicals.
light. The photoexcitated state, most often the triplet stateof
4.4. Pollution and other external substances
the sensitizer, is the key photoreactive intermediate and exerts
photodamage throughdirect reaction with substrate molecules Air pollutants such as asbestos, benzene, carbon monoxide,
(type I photosensitization) or activation ofmolecular oxygen chlorine,formaldehyde, ozone, one, tobacco smoke, and
by energy transfer reactions (type II photosensitization) toluene,Chemical solvents such as cleaning products, glue,
(Wondraket al., 2006). 1O2 is anexcited state molecule formed paints, and paint thinners, Over
Over-the-counter and prescribed
by direct energy tranfer between the excited sensitizer medications, Perfumes,, Pesticides
Pesticides, Water pollutants suchas
andground state 3O2. Less than 1% of triplet oxygen is chloroform and other trihalomethanes caused by
converted in parallel to superoxide anion(O2‐). The formation chlorination,Cosmic radiation, Electromagnetic fields,Medical
of O2‐ as a precursor of H2O2 occurs via electron transfer via and dental x-rays,
rays, Radon gas, Solar radiation,the food
productionof a sensitizer radical cation, or after an containing farm chemicals, like fertilizers and pesticides,
intermediate reduction of the sensitizer with asubstrate processed foods containing high levels of lipid peroxides, are
followed by the single electron reduction of O2 (Klotzet al., all potent generator of free radicals.
2003; Croftset a., 2008).
4.5. General factors: Aging,
ging, Metabolism, Stress.
3.3. Other cellular ROS sources
4.6. Dietary factors: Additives, alcohol, coffee, foods of
The most studied producers of O2.‐ by oxidizing unsaturated animal origin, foods that have been barbecued, broiled,fried,
fatty acids and xenobiotics are cytochrome P450 and the b5 grilled, or otherwise cooked at high, temperatures, foods that
family of enzymes (Thannickal and Fanburg,
Fanburg 2000). Electrons have been browned or burned, herbicides,hydro
herbicides,hydrogenated
leaking from nuclear membrane cytochrome oxidases and vegetable oils, pesticides, sugar.
electron transport systems may give rise to ROS. In addition
to intracellular membrane‐associated
associated oxidases, aldehyde 4.7. Toxins: Carbon tetrachloride, Paraquat, Benzo (a) pyrene,
oxidase, dihydroorotate dehydrogenase, flavoprotein Aniline dyes, Toluene
dehydrogenase and tryptofan dioxygenase can all generate
4.8.Drugs: Adriamycin, Bleomycin, Mitomycin C,
ROS during catalytic cycling. pH‐dependent
dependent cell wall
Nitrofurantoin, Chlorpromazine
peroxidases, germin‐like
like oxalate oxidases and amine oxidases
have been proposed as a source of H2O2 in the apoplast of
plant cells (Bolwell andWoftastek, 1997).. Glycolate oxidase,
D‐amino
amino acid oxidase, urate oxidase, flavin oxidase, L‐α‐
L
hydroxy acid oxidase, and fatty acyl‐‐CoA oxidase are
important sources of total cellular H2O2 production in
peroxisomes (Foster and Stamler, 2004).. Auto‐oxidation
Auto of
small molecules such as epinephrine, flavins, and
hydroquinones can also be an important source of intracellular
ROS production (Foster and Stamler,, 2004).
2004)
4. Production route of free radicals
Production of free radicals in the body is continuous and
inescapable. The basic causes include the following
(Lippincott Williams and Wilkins Instructor’s Resource,
Resource
2008): Figure 2. Free radical formation

4.1. The immune system 5. Formation of radicals in biological systems and

Immune system cells deliberately create oxy-radicals
oxy and consequences ofoxidation of biological molecules
ROS (Reactive oxygen species) as weapons. 5.1. Oxidative damage to protein and DNA
4.2. Energy production Proteins can be oxidatively modified in three ways: oxidative
During energy-producing
producing cell generates continuously and modification of specific amino acid, free radical mediated
abundantly oxy-radicals
radicals and ROS as toxic waste. The cell peptide cleavage, and formation of protein cross
cross-linkage due
includes a number of metabolic processes, each of which can to reaction with lipid peroxidation products. Protein
containing amino acids such as methionine, cyst
cystein, arginine,
International Journal of Innovation Sciences and Research 221

and histidine seem to be the most vulnerable to oxidation  Oxygenases (eg. COX: cyclo cyclo-oxygenases, LOX:
(Freemanet al., 1982). Free radical mediated protein lipoxygenase) for the generation of prostaglandins and
modification increases susceptibility to enzyme proteolysis. leukotrienes, which have many regulatory functions
Oxidative damage to protein products may affect the activity (Yoshikawaet al., 2000)
of enzymes, receptors, and membrane transport. Oxidatively
damaged protein products may contain very reactive
re groups
that may contribute to damage to membrane and many cellular Table 1. Reactive oxygen and nitrogen species of biological
functions. Peroxyl radical is usually considered to be free interest
radical species for the oxidation of proteins. ROS can damage
proteins and produce carbonyls and other amino acids
modification
ation including formation of methionine sulfoxide and
protein carbonyls and other amino acids modification
including formation of methionine sulfoxide and protein
peroxide. Protein oxidation affects the alteration of signal
transduction mechanism, enzyme activity,
ctivity, heat stability, and
proteolysis susceptibility, which leads to aging.
5.2. Lipid peroxidation
Oxidative stress and oxidative modification of biomolecules
are involved in a number of physiological and
pathophysiological processes such as aging, artheroscleosis,
a
inflammation and carcinogenesis, and drug toxicity. Lipid
peroxidation is a free radical process involving a source of
secondary free radical, which further can act as second
messenger or can directly react with other biomolecule,
enhancing biochemical lesions. Lipid peroxidation occurs on
polysaturated fatty acid located on the cell membranes and it
further proceeds with radical chain reaction. Hydroxyl radical
is thought to initiate ROS and remove hydrogen atom, thus
producing lipid radicall and further converted into diene
conjugate. Further, by addition of oxygen it forms peroxyl 7.Antioxidant protection system
radical; this highly reactive radical attacks another fatty acid
forming lipid hydroperoxide (LOOH) and a new radical. Thus To protect the cells and organ systems of the body against
lipid peroxidation is propagated. Due to lipid peroxidation, a reactive oxygen species (ROS), humans have evolved a highly
number of compounds are formed, for example, alkanes, sophisticated and complex antioxidant protection system. It
malanoaldehyde, and isoprotanes. These compounds are used involves a variety of components, both endogenous and
as markers in lipid peroxidation assay and have been verified exogenous in origin, that function interactively and
in many diseases such as neurogenerative diseases, ischemic
ischem synergistically to neutralize free radicals (Table 1) (Mark
et al.,
reperfusion injury, and diabetes (Lovellet al 1995). Percival, 1998) these components include:

5.3. Oxidative damage to DNA 7.1.1. Endogenous Antioxidants

Many experiments clearly provide evidences that DNA and  Bilirubin

RNA are susceptible to oxidative damage. It has been reported  Thiols, e.g., glutathione, lipoic acid, N
N-acetyl cysteine
that especially in aging and cancer, DNA is considered as a  NADPH and NADH
major target (Wooet al., 1998). Oxidative nucleotide as
 Ubiquinone (coenzyme Q10)
glycol, dTG, and 8-hydroxy-2-deoxyguanosine
deoxyguanosine is found to be
 Uric acid.
increased during oxidative damage to DNA under UV
radiation or free radical damage. It has been reported that 7.1.2. Enzymes
mitochondrial DNA are more susceptible to oxidative damage
that have role in many diseases including cancer. It has been  copper/zinc and manganese
manganese-dependent superoxide
suggested that 8-hydroxy-2-deoxyguanosine
deoxyguanosine can be used as dismutase
Hattoriet al., 1997).
biological marker for oxidative stress (Hattori  iron-dependent catalase
 selenium-dependent
dependent glutathione peroxidase
6. The important beneficial role of free radicals
7.2. Dietary Antioxidants
 Generation of ATP (universal energy currency) from ADP
in the mitochondria: oxidative phosphorylation  Vitamin C
 Detoxification of xenobiotics by Cytochrome P450  Vitamin E
(oxidizing enzymes)  Beta carotene and other carotenoids and oxycarotenoids,
 Apoptosis of effete or defective cells e.g., lycopene and lutein
 Killing of micro-organisms
organisms and cancer cells by  Polyphenols, e.g., flavonoids, flavones, flavonol’s, and
macrophages and cytotoxic lymphocytes Proanthocyanidins
International Journal of Innovation Sciences and Research 222

7.3. Metal Binding Proteins lysine residues rather than lipid oxidation. Biochemical
Journal, 302(1) 297‐304.
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 Ceruloplasmin (copper) Hughes, E. J.and Jones, O. T. 1996. Expression of
 Metallothionein (copper) phagocyte NADPH oxidase components in human
 Ferritin (iron) endothelial cells. American Journal of Physiology, 271(4
 Myoglobin (iron) Pt 2) H1626‐H1634.
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