From the Department of Critical Care Medicine, Safar Center for Resuscitation Research, Center for Free Radical and Antioxidant Health, University of Pittsburgh School of Medicine, and the Children’s Hospital of Pittsburgh, Pittsburgh, PA.
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DefinitionsA free radical is defined as any species that contains one or more unpaired electrons (1). Reactive oxygen species (ROS) is a collective term that includes both oxygen radicals, such as superoxide (O2·−), hydroxyl (OH·), peroxyl (RO2·), and hydroperoxyl (HO2·) radicals, and certain nonradical oxidizing agents, such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and ozone (O3), that can be converted easily to into radicals (1). ROS are implicated in the pathogenesis of sepsis (2). However, ROS are also produced during normal metabolism and are involved in enzymatic reactions, mitochondrial electron transport, signal transduction, activation of nuclear transcription factors, gene expression, and the antimicrobial action of neutrophils and macrophages.In general, the reducing environment inside cells helps to prevent free radical-mediated damage. This reducing environment is maintained by the action of antioxidant enzymes and substances, such as superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione, ascorbate (vitamin C), α-tocopherol (vitamin E), and thioredoxin. Alterations in the redox state and depletion of antioxidants by exposure to oxidants lead to oxidative stress and resultant oxidative injury.The oxygen molecule (dioxygen; O2) qualifies as a radical because (in its ground state) it has two unpaired electrons. From a quantum mechanical standpoint, the electron spin quantum number for ground state dioxygen is three (i.e., oxygen is a triplet species). Since most stable organic molecules are in singlet state (electron spin quantum number equal to one), the reaction of ground state oxygen with cellular constituents is “spin forbidden” even though oxygen is considered a powerful oxidizing agent. To overcome spin restriction, oxygen prefers to accept electrons one at a time, and the sequential addition of electrons leads to formation of ROS. Acceptance of a single electron by an oxygen molecule forms O2·−, which has one unpaired electron. Superoxide itself has limited reactivity. It is capable of inactivating few enzymes directly. The reduced nicotinamide adenine dinucleotide phosphate dehydrogenase complex of the mitochondrial electron transport chain is one of the enzymes shown to be a direct target for O2·− attack (3).Removal of excess O2·− by SOD is an important defense mechanism in aerobic organisms (4). The isoforms of SOD convert O2·− into H2O2:H2O2 is a poorly reactive oxidizing agent. Unlike O2·−, however, H2O2 crosses cell membranes easily. H2O2 does not contain unpaired electrons; therefore, it is not a radical. H2O2 may act as a metabolic signal under certain circumstances, possibly by oxidizing specific protein thiol groups (1). H2O2 can be removed by action of catalases via a reaction where oxygen and two molecules of water are formed (Eq. 2) and by peroxidases via reduction of H2O2 to two molecules of water using different reductants, such as glutathione, ascorbate, thioredoxin, reduced nicotinamide adenine dinucleotides, and phenolic compounds (Eq. 3).Overall, O2− and H2O2 have limited chemical reactivity, but they can generate highly reactive hydroxyl radicals (OH·). Transition metals such as Fe(II) and Cu(I) react with H2O2 to form OH· by the Fenton reactionSuperoxide can reduce Fe (III) and Cu (II):The sum of reactions 2 and 3 isa reaction called the transition metal catalyzed Haber-Weiss reaction.