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The dark side of oxigen
How free radicals cause damage and disease?
Source of Free Radicals:
Free radicals have two principle sources: endogenous sources and exogenous sources. Endogenous sources of free radicals include those that are generated intracellularly, acting within the cell, and those that are formed within the cell, but are released into the surrounding area. These intracellular free radicals result from auto-oxidation and consequent inactivation of small molecules such as reduced thiols and flavins. They may also occur as a result of the activity of certain oxidases, lipoxygenases, cyclo-oxygenases, dehydrogenases and peroxidases. Electron transfer from metals such as iron to oxygen-containing molecules can also initiate free radical reactions Paradoxically; antioxidants may also produce free radicals.
A wide range of free radical molecular species are endogenous. The singlet oxygen is not a free radical but is nevertheless a reactive oxygen species and capable of causing tissue damage (Foote, 1976; Halstead, 1979; Machlin and Bendich, 1987; and Levine and Kidd, 1994).
Exogenous sources of free radicals include irradiation, chemical pollutants, and some medications, including cancer chemotherapeutic agents. The exogenous sources of free radicals resulting from ionizing radiation play a major role in free radical production. The energy transferred into water from ionizing particles ionizes the water molecule. The water ions produced dissociate yielding free radicals (Pizzarello and Witcofski, 1975; Machlin and Bendich, 1987; Levine and Kidd 1994).
Production of Free Radicals:
Free radicals are produced in a number of ways in biological systems.
- Exposure to ionizing radiation is a major cause of free radical production. When irradiated water is ionized, and electron is removed from the molecule, leaving behind an ionized water molecule. The damaging species resulting from the radiolysis of water are the free radicals H× and OH× and eaq (hydrated electrons). They are highly reactive and have a lifetime on the order of 10 -9 to 10 -11 seconds. The hydroxyl radical is extremely reactive and is carcinogenic. Since water presents the largest number of target molecules in a cell, most of the energy transfer goes on in water when a cell is irradiated, rather then the solute consisting of protein, carbohydrate, nucleic acid, and bioinorganic molecules. Oxygen is an excellent electron acceptor and can combine with the hydrogen radical (H×) to form a peroxyl radical (H× + O2 ® HO2). Hydrogen peroxide is toxic and when present in sufficient quantities can interfere with normal cellular metabolism.
- Enzymes and transport molecules also generate free radicals as a normal consequence of their catalytic function. Examples of two enzymes which have been extensively studied in biological systems are xanthine oxidase and aldahyde oxidase. Both of these enzymes generate the superoxide anion radical (O2×) by adding a single electron to molecular oxygen. Other enzymes may use superoxide for their normal catalytic activity. The mitochondria of cells are the major source of endogenous free radical generation and are utilized in the synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP), the primary energy currency of the body. Thus, the mitochondrion serves as the powerhouse of the cell and contains most of the respiratory enzymes of the citric acid cycle.
- Auto-oxidation reactions produce free radicals from the spontaneous oxidation of biological molecules involved in nonenzymatic electron transfers. Although these reactions are a normal part of cellular metabolism, these free radicals may, under certain adverse conditions, achieve serious clinical significance.
- Examples of compounds that may be auto-oxidised in the body include thiols, hydroquines, catecholamines, flavins, ferredoxins, and hemoglobin. In all of these auto-oxidation reactions, superoxide is the main free radical species that is produced initially. The processes involved in oxidation-reduction reactions are of immense biochemical importance since the transfer of electrons is the means by which the body derives most of its free energy. In oxidation, electrons are lost; in reduction, electrons are gained.
- Toxic metals may produce free radicals in
the body. The metals (copper, iron, cadmium, arsenic, mercury,
chromium, antimony, beryllium, thallium, silver, and nickel)
are believed to derive their toxic effects from their inherent
ability to transfer electrons, which is also an expression
of their capability to generate free radicals. Transition
metals (scandium, titanium, vanadium, chromium, manganese,
iron, cobalt, nickel, copper, and zinc) usually promote
free radical reactions. These free radicals can adversely
affect cellular health by producing lipid peroxidation of
intracellular membranes and cross linkages of membrane macromolecules.
Heavy-metal free radicals have a tendency to form covalent bonds with sulfhydral groups. In this manner they are able to modify the functions of many enzymes, not to mention nonenzymatic antioxidant compounds, such as glutathione, which depend on these groups for their biological activity.
No attempt has been made to review the subject of heavy-metal intoxications in depth other than to touch on their free radical activity and their deleterious effects on the immune system. The toxic effects of heavy metals have been well-documented (Friberg et al., 1979; Luckey and Venogopal, 1977; Venugopal and Luckey, 1975). Toxic metals are known to affect cell membrane permeability, subcellular organelles, and the structure and function of proteins and nucleic acid.
Toxic metals may affect the biosynthetic formation of hormones and depress enzymatic and other metabolic processes. These metals may also stimulate those metabolic functions that lead to free radical production and carcinogenesis. The following metals have been found to have a deleterious effect on the immune system and contribute to atherogenesis.
