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Free Radicals, Types, Sources and Damaging Reactions

Submitted by Dr. Tamer Fouad, M.D.


Free radicals are a chemical species that possess an unpaired electron in the outer shell of the molecule.


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Oxidative mechanisms in carcinogenesis

Sources of free radicals

Endogenous sources


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).

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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