Home  Merimed  Vitaminsprays
free radical

Description

They are a chemical species that possess an unpaired electron in the outer (valence) shell of the molecule. This is the key factor in the structure of this species (Greenwald, 1991; Halliwell, 1995) and is the reason why they are highly reactive. This species is in reality composed of a group of molecular fragments that are capable of independent existence. (Cheeseman and Slater, 1993).

The fact that they are highly reactive means that they have low chemical specificity; i.e. they can react with most molecules in its vicinity. This includes proteins, lipids, carbohydrates and DNA. It also means that in trying to gain stability by capturing the needed electron they don't survive in their original state for very long and quickly react with their surroundings. Hence, free radicals attack the nearest stable molecule, "stealing" its electron. When the "attacked" molecule loses its electron, it becomes a free radical itself, beginning a chain reaction. Once the process is started, it can cascade, finally resulting in the disruption of a living cell.

Free radicals are produced continuously in cells either as by-products of metabolism or deliberately as in phagocytosis (Cheeseman and Slater, 1993).

Free radicals can be generated both in-vivo and in-vitro by one of the following mechanisms:

1.     Homolytic cleavage of a covalent bond, in which a normal molecule fragments in two, each fragment retaining one of the paired electrons.  Homolytic cleavage occurs less commonly in biological systems, as it requires high-energy input from ultra-violet light, heat or ionising radiation.

2.     Loss of a single electron from a normal molecule.

3.     Addition of an electron to a normal molecule.

A fundamental fact about free radicals is that the unpaired electrons in their outer shells do not affect the charge on the resultant molecule. Free radicals can be negatively charged, positively charged or electrically neutral (Cheeseman and Slater, 1993). This is because charge is concerned with the number of negatively charged electrons in relation to the positively charged protons whereas free radicals are related only to the spatial arrangement of the outer electron. The unpaired electron may have been gained on top of a neutral molecule making it negative; alternatively, it may have resulted from the loss of an electron from the same molecule resulting in a positive charge. Likewise, if the original molecule were not neutral to begin with the addition or removal of an unpaired electron would result in a neutral charge.

Functions

With the exception of the unusual circumstances such as ionising radiation, ultraviolet light & other forms of high energy exposure, free radicals are produced, in cells, in general by electron transfer reactions, which can be enzymatically mediated or nonenzymatically mediated. The production of free radicals in cells can happen both accidentally or deliberately. An example of deliberate reactions is the superoxide generated by activated phagocytes and in catalytic reactions e.g. Ribonucleotide reductase (Stubbe J, 1990 and Reichard P, Ehrenberg A, 1983). An example of accidental generation of free radicals would be the leakage of superoxide, hydrogen peroxide & other ROS at the interface of the bacterium & the activated phagocyte (Babior BM, 1978). However the major source of free radicals under normal circumstances is the electron leakage that happens from electron transport chains, such as those in the mitochondria & endoplasmic reticulum, to molecular oxygen generating superoxide.

Sources

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).

Exogenous sources

Drugs:A number of drugs can increase the production of free radicals in the presence of increased oxygen tensions. The agents appear to act additively with hyperoxia to accelerate the rate of damage. These drugs include antibiotics that depend on quinoid groups or bound metals for activity (nitrofurantoin), antineoplastic agents as bleomycin, anthracyclines (adriamycin) (Fisher, 1988) and methotrexate, which possess pro-oxidant activity (Gressier et al. 1994). In addition radicals derived from penicillamine, phenylbutazone, some fenamic acids and the aminosalicylate component of sulphasalazine might inactivate protease and deplete ascorbic acid accelerating lipid peroxidation (Grisham et al. 1992; Halliwel et al. 1992a; Evans et al. 1994).

Radiation:Radiotherapy may cause tissue injury that is  caused by free radicals. Electromagnetic radiation (X rays, gamma rays) and particulate radiation (electrons, photons, neutrons, alpha and beta particles) generate primary radicals by transferring their energy to cellular components such as water. These primary radicals can undergo secondary reactions with dissolved oxygen or with cellular solutes.

Tobacco smoking:Oxidants in tobacco exist in sufficient amounts to suggest that they play a major role in injuring the respiratory tract. It has been shown that tobacco smoke oxidants severely deplete intracellular antioxidants in the lung cells in vivo by a mechanism that is related to oxidant stress. It has been estimated that each puff of smoke has an enormous amount of oxidant materials. These include aldehydes, epoxides, peroxides, and other free radicals that may be sufficiently long lived as to survive till they cause damage to the alveoli. In addition nitric oxide, peroxyl radicals and carbon centred radicals are present in the gas phase. In addition it also contains other relatively stable radicals in the tar phase. Examples of radicals in the tar phase include the semiquinone moieties derived from various quinones and hydroquinones. Again micro-haemorrhages are most probably the cause of iron deposition found in smokers' lung tissue. Iron in this form leads to the formation of the lethal hydroxyl radical from hydrogen peroxide. It was also found that smokers have elevated amounts of neutrophils in the lower respiratory tract that could contribute to a further elevation of the concentration of free radicals.

Inorganic particles:Inhalation of inorganic particles also known as mineral dust (e.g. asbestos, quartz, silica) can lead to lung injury that seems at least in part to be mediated by free radical production. Asbestos inhalation has been linked to an increased risk of developing pulmonary fibrosis (asbestosis), mesothelioma and bronchogenic carcinoma. Silica particles as well as asbestos are phagocytosed by pulmonary macrophages. These cells then rupture, releasing proteolytic enzymes and chemotactic mediators causing infiltration by other cells such as neutrophils, thus initiating an inflammatory process (Kehrer JP, Mossman BT, Sevanian A, Trush MA, Smith MT; 1988), that leads to increased production of free radicals and other reactive oxygen species (Heffner and Repine, 1989; Vallyathan et al. 1988). Furthermore, asbestos fibres contain iron, which may have been derived form haemoglobin liberated from micro-haemorrhages. This iron can stimulate the formation of hydroxyl radicals.

Gases:Ozone is not a free radical but a very powerful oxidising agent. Ozone (O3) contains two unpaired electrons and degrades under physiological conditions to ·OH, suggesting that free radicals are formed when ozone reacts with biological substrates. In support of this hypothesis, ozone can generate lipid peroxidation in-vitro, although similar findings in-vivo have not been demonstrated.

Others:Fever, excess glucocorticoid therapy and hyperthyroidism decrease oxygen tolerance in experimental animals. The decrease is attributable to the increased generation of oxygen-derived radicals that accompanies increased metabolism. In addition, a wide variety of environmental agents including photochemical air pollutants as pesticides, solvents, anaesthetics, exhaust fumes and the general class of aromatic hydrocarbons, also cause free radical damage to cells.