A continuous and unavoidable threat

May be produced accidentally but unavoidably:

e.g., leakage of electrons from mitochondrial respiratory chain; autoxidation of catecholamines; during post-ischaemic reperfusion; some photosensitizing reactions

Figure 2 Sources of reactive oxygen species found in vivo.

Can be purposeful and directed:

e.g., during respiratory burst of activated phagocytes; as nitric oxide (produced for vasodilation); for cell signalling and gene activation

May serve no purpose, but are generally unavoidable and often damaging:

e.g., from food, pollutants, cytochrome P-450 reactions; some photosensitizing reactions; ionizing radiation

Figure 2 Sources of reactive oxygen species found in vivo.

during the respiratory burst of activated phagocytic white cells (macrophages, neutrophils, and monocytes). Activated phagocytes produce large amounts of superoxide and hypochlorous acid for microbial killing. The ROS nitric oxide is produced constitu-tively and inducibly, is a powerful vasodilator, and is vital for the maintenance of normal blood pressure. Nitric oxide also decreases platelet aggregabil-ity, decreasing the likelihood of the blood clotting within the circulation. Hydrogen peroxide is produced enzymatically from superoxide by the action of the superoxide dismutases (SODs) and is recognized increasingly as playing a central role in cell signalling and gene activation. Nonetheless, while some ROS are physiologically useful, they are damaging if they accumulate in excess as a result of, for example, acute or chronic inflammation or ischaemia.

Accidental, but unavoidable, production of ROS occurs during the passage of electrons along the mito-chondrial electron transport chain. Leakage of electrons from the chain leads to the single-electron reduction of oxygen, with the consequent formation of superoxide. This can be regarded as a normal, but undesirable, by-product of aerobic metabolism. Around 1-3% of electrons entering the respiratory chain are estimated to end up in superoxide, and this results in a large daily ROS load in vivo. If anything increases oxygen use, such as exercise, then more ROS will be formed, and oxidant stress may increase owing to a pro-oxidant shift. Significant amounts of ROS are also produced during the metabolism of drugs and pollutants by the mixed-function cyto-chrome P-450 oxidase (phase I) detoxifying system and as a consequence of the transformation of xanthine dehydrogenase to its truncated oxidase form, which occurs as a result of ischemia. This causes a flood of superoxide to be formed when the oxygen supply is restored. In addition, if free iron is present (as may happen in iron overload, acute intra-vascular hemolysis, or cell injury), there is a risk of a cycle of ROS production via iron-catalyzed 'autoxidation' of various constituents in biological fluids, including ascorbic acid, catecholamines, dopamine, hemoglobin, flavins, and thiol compounds such as cysteine or homocysteine. Preformed reactive species in food further contribute to the oxidant load of the body, and ROS are also produced by pathological processes and agents such as chronic inflammation, infection, ionizing radiation, and cigarette smoke. Breathing oxygen-enriched air results in enhanced production of ROS within the lungs, and various toxins and drugs, such as aflatoxin, acetominophen, carbon tetrachloride, chloroform, and ethanol, produce reactive radical species during their metabolism or detoxification and excretion by the liver or kidneys. Clearly, all body tissues are exposed to ROS on a regular or even constant basis. However, sites of particularly high ROS loads within the human body include the mitochondria, the eyes, the skin, areas of cell damage, inflammation, and post-ischemic reperfusion, the liver, the lungs (especially if oxygen-enriched air is breathed), and the brain.

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