A toxic effect in a living organism caused by a species of oxygen. Oxygen has two aspects—one benign and the other malignant (see illustration). Therefore, organisms that avail themselves of the enormous metabolic advantages provided by dioxygen (O2) must defend themselves against its toxicity. The complete reduction of one molecule of O2 to two molecules of water (H2O) requires four electrons; thus, intermediates must be encountered during the reduction of O2 by the univalent pathway. The intermediates of O2 reduction, in the order of their production, are the superoxide radical (O2−), hydrogen peroxide (H2O2), and the hydroxyl radical (HO·). See also: Biological oxidation; Hydrogen peroxide; Hydroxyl; Oxygen; Superoxide chemistry; Toxicology
The intermediates of oxygen reduction, rather than O2 itself, are probably the primary causes of oxygen toxicity. It follows that defensive measures must deal with these intermediates. The superoxide radical is eliminated by enzymes that catalyze the following reaction:
These enzymes, known as superoxide dismutases, have been isolated from a wide variety of living things, and they have been found to contain iron, manganese, or both copper and zinc at their active sites. Notably, elimination of superoxide dismutases from oxygen-tolerant bacteria renders them intolerant of O2, whereas exposure to elevated levels of O2 elicits an adaptive increase in the biosynthesis of these enzymes. Both of these responses suggest that O2− is a major cause of the toxicity of O2. See also: Enzyme
Hydrogen peroxide (H2O2) must also be eliminated, and this is achieved by two enzymatic mechanisms. The first of these is the dismutation of H2O2 into water and oxygen; this process is catalyzed by catalases. The second is the reduction of H2O2 into two molecules of water at the expense of a variety of reductants; this process is catalyzed by peroxidases. Plant peroxidases are hemoenzymes, that is, enzymes that contain heme as a prosthetic group; they can use ascorbate, phenols, or amines as the reductants of H2O2. A selenium-containing peroxidase that uses the tripeptide glutathione as the reductant of H2O2 can be found in animal cells. See also: Glutathione
The multiplicity of superoxide dismutases, catalases, and peroxidases, along with the great catalytic efficiency of these enzymes, provides a formidable defense against O2− and H2O2. If these first two intermediates of O2 reduction are eliminated, the third intermediate (HO·) will not be produced. No defense is perfect, however, and some HO· is produced; therefore, its deleterious effects must be minimized. This is achieved to a large extent by antioxidants, which prevent free-radical chain reactions from propagating. For example, the human organism depends upon (1) α-tocopherol (vitamin E) to prevent such chain reactions within the hydrophobic core of membranes and (2) ascorbate and glutathione to serve the same end in the aqueous compartments of cells. See also: Antioxidant; Chain reaction (chemistry); Free radical; Vitamin E
Some damage due to oxygen-derived free radicals is sustained on a continuing basis, in spite of the existing multilayered defenses, and must be repaired. Thus, there are enzymes that recognize and hydrolyze oxidatively damaged proteins, and there are other enzymes that repair oxidative damage to deoxyribonucleic acid (DNA). Indeed, analysis of human urine for oxidized pyrimidines, which are removed from DNA during such repair, indicates the occurrence of at least 1000 such events per cell per day. See also: Pyrimidine
Overall, the apparent comfort in which aerobic organisms live in the presence of an atmosphere that is 20% O2 is the result of a complex and effective system of defenses against this peculiar gas. Indeed, these defenses are easily overwhelmed, and overt symptoms of oxygen toxicity become apparent when organisms are exposed to 100% O2. For example, a rat maintained in 100% O2 will die in 2 to 3 days.