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Free Radicals, Types, Sources
and Damaging Reactions
Submitted by Dr. Tamer
Fouad, M.D.
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Free radicals are a chemical species that possess
an unpaired electron in the outer shell of the molecule.
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Sources of free radicals
Endogenous sources
Autoxidation:
Autoxidation is a by-product
of the aerobic internal milieu. Of the molecules that undergo
autoxidation come catecholamines, haemoglobin, myoglobin, reduced
cytochrome C and thiol. Autoxidation of any of the above molecules
in a reaction results in the reduction of the oxygen diradical
and the formation of reactive oxygen species. Superoxide is
the primary radical formed. Ferrous ion (Fe II) also, can have
its electron stolen from it by oxygen to produce superoxide
and Fe III, by the process of autoxidation (Fridovich,
1983 and 1995).
Enzymatic oxidation:
A variety of enzyme
systems is capable of generating significant amounts of free
radicals, including xanthine oxidase (activated in ischemia-reperfusion),
prostaglandin synthase, lipoxygenase, aldehyde oxidase, and
amino acid oxidase. The enzyme myeloperoxidase produced in activated
neutrophils, utilizes hydrogen peroxide to oxidize chloride
ions into the powerful oxidant hypochlorous acid (HOCl) (Halliwell
et al. 1995).
Respiratory burst:
Is a term used to describe
the process by which phagocytic cells consume large amounts
of oxygen during phagocytosis. Between 70 and 90% of this oxygen
consumption can be accounted for in terms of superoxide production
(Baboir BM; 1984).
These phagocytic cells possess a membrane bound flavoprotein
cytochrome-b-245 NADPH oxidase system. Cell membrane enzymes
such as the NADPH-oxidase exist in an inactive form. It is the
exposures to immunoglobulin-coated bacteria, immune complexes,
complement 5a, or leukotriene, however, which activate the enzyme
NADPH-oxidase. This activation initiates a respiratory burst
at the cell membrane to produce superoxide (Baboir
BM, 1978). H2O2 is then formed from
superoxide by dismutation with subsequent generation of ?OH
and HOCl by bacteria (Rosen
H, Rikata R, Waltersdorph AM, Klebanoff S; 1987).
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Subcellular organelles:
Organelles such as mitochondria,
chloroplasts, microsomes, peroxisomes and nuclei have been shown
to generate O2?⁻
and this is easily demonstrated
after the endogenous superoxide dismutase has been washed away
(Asada and Kiso, 1973).
Mitochondria are the main cellular organelle for cellular oxidation
reactions and the main source of reduced oxygen species in the
cell. The leaks in mitochondrial electron transport system allow
O2 to accept a single electron forming O2?⁻
(Kalra et al. 1994; Haliwell,
1995). It has been shown that superoxide production by the
mitochondria increases in two conditions; either when the oxygen
concentration is greatly increased or when the respiratory chain
becomes fully reduced (as happens during ischemia).
Microsomes are responsible
for 80% of the H2O2 produced in vivo at
100% hyperoxia sites (Jamieson
et al. 1986). Peroxisomes are known to produce H2O2,
but not O2?⁻,
under physiologic conditions (Chance
et al. 1979). Although the liver is the primary organ where
peroxisomal contribution to the overall H2O2
production is significant, other organs that contain peroxisomes
are also exposed to these H2O2 -generating
mechanisms. Peroxisomal oxidation of fatty acids has recently
been recognized as a potentially important source of H2O2
production with prolonged starvation.
Transition metals ions:
Iron and copper play
a major role in the generation of free radicals injury and the
facilitation of lipid peroxidation. Transition metal ions participate
in the Haber-Weiss reaction that generates ?OH from O2?⁻
and H2O2.
H2O2
+ Fe2⁺
? ?OH + OH⁻
+ Fe3⁺
The Haber-Weiss reaction
accelerates the nonenzymatic oxidation of molecules such as
epinephrine and glutathione that generates O2?⁻
and H2O2 and subsequently ?OH.
Ischemia reperfusion injury:
Ischemia confers a number
of effects all contributing to the production of free radicals.
Normally xanthine oxidase is known to catalyse the reaction
of hypoxanthine to xanthine and subsequently xanthine to uric
acid. This reaction requires an electron acceptor as a cofactor.
During ischemia two factors occur, first the production of xanthine
and xanthine oxidase are greatly enhanced. Second, there is
a loss of both antioxidants superoxide dismutase and glutathione
peroxidase. The molecular oxygen supplied on reperfusion serves
as an electron acceptor and cofactor for xanthine oxidase causing
the generation of the O2?⁻and
H2O2. Strenuous exercise has been proposed
to activate xanthine oxidase-catalysed reactions and generate
free radicals in skeletal muscle and myocardium.
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