Mechanisms of superoxide radical-mediated toxicity

Free radicals generated from metabolism of foreign compounds can have extremely detrimental consequences on cell function and survival. Due to their high reactivity, free radicals may potentially perturb a wide spectrum of important cellular macromolecules such as nucleic acids, proteins, lipids and polysaccharides. Recently, the toxicity of several xenobiotics has been suggested to be mediated by formation of free radicals derived from reduction of molecular oxygen, forming superoxide anion (O(2)) and hydroxyl radical (OH .). For example, the pulmonary toxicity of the bipyridylium herbicide paraquat has been attributed to an enzymatically catalyzed one-electron redox cycling of the parent molecule, resulting in generation of O(2). Examples of other compounds that are subject to redox cycling with associated O(2) formation are those agents containing quinone or aromatic nitro structural elements. An important aspect of free-radical-mediated toxicity is that it is moderated by several cellular defense mechanisms including superoxide dismutase, catalase, glutathione peroxidase, vitamin E and reduced glutathione. Thus, toxicity mediated by free radical generation may not occur unless defense mechanisms are overwhelmed by radical production.