Oxidative stress: the paradox of aerobic life (1995)

The paradox of aerobic life, or the 'Oxygen Paradox', is that higher eukaryotic aerobic organisms cannot exist without oxygen, yet oxygen is inherently dangerous to their existence. This 'dark side' of oxygen relates directly to the fact that each oxygen atom has one unpaired electron in its outer valence shell, and molecular oxygen has two unpaired electrons. Thus atomic oxygen is a free radical and molecular oxygen is a (free) bi-radical. Concerted tetravalent reduction of oxygen by the mitochondrial electron-transport chain, to produce water, is considered to be a relatively safe process; however, the univalent reduction of oxygen generates reactive intermediates. The reductive environment of the cellular milieu provides ample opportunities for oxygen to undergo unscheduled univalent reduction. Thus the superoxide anion radical, hydrogen peroxide and the extremely reactive hydroxyl radical are common products of life in an aerobic environment, and these agents appear to be responsible for oxygen toxicity. To survive in such an unfriendly oxygen environment, living organisms generate--or garner from their surroundings--a variety of water- and lipid-soluble antioxidant compounds. Additionally, a series of antioxidant enzymes, whose role is to intercept and inactivate reactive oxygen intermediates, is synthesized by all known aerobic organisms. Although extremely important, the antioxidant enzymes and compounds are not completely effective in preventing oxidative damage. To deal with the damage that does still occur, a series of damage removal/repair enzymes, for proteins, lipids and DNA, is synthesized. Finally, since oxidative stress levels may vary from time to time, organisms are able to adapt to such fluctuating stresses by inducing the synthesis of antioxidant enzymes and damage removal/repair enzymes. In a perfect world the story would end here; unfortunately, biology is seldom so precise. The reality appears to be that, despite the valiant antioxidant and repair mechanisms described above, oxidative damage remains an inescapable outcome of aerobic existence. In recent years oxidative stress has been implicated in a wide variety of degenerative processes, diseases and syndromes, including the following: mutagenesis, cell transformation and cancer; atherosclerosis, arteriosclerosis, heart attacks, strokes and ischaemia/reperfusion injury; chronic inflammatory diseases, such as rheumatoid arthritis, lupus erythematosus and psoriatic arthritis; acute inflammatory problems, such as wound healing; photo-oxidative stresses to the eye, such as cataract; central-nervous-system disorders, such as certain forms of familial amyotrophic lateral sclerosis, certain glutathione peroxidase-linked adolescent seizures, Parkinson's disease and Alzheimer's dementia; and a wide variety of age-related disorders, perhaps even including factors underlying the aging process itself. Some of these oxidation-linked diseases or disorders can be exacerbated, perhaps even initiated, by numerous environmental pro-oxidants and/or pro-oxidant drugs and foods. Alternatively, compounds found in certain foods may be able to significantly bolster biological resistance against oxidants. Currently, great interest centres on the possible protective value of a wide variety of plant-derived antioxidant compounds, particularly those from fruits and vegetables.