Oxidative Stress: Pathogenetic Mechanisms

Abstract

Radical and nonradical 'reactive oxygen species (ROS)' are normally occurring intermediates of aerobic cellular metabolism. Under physiologic conditions, they are kept from causing noticeable damage by antioxidant enzymes and small molecular weight compounds. Oxidative stress develops when antioxidants are overwhelmed by ROS. This may occur via overproduction of the latter and/or by deficiency of anti­ oxidant defense. ROS in excess, especially the highly reactive hydroxyl radical (HO-), which is usually generated with the catalytic help of transition metals such as ferrous ions, can attack virtually all biological structures. Consequences may be func­ tionally relevant when sensitive macromolecules are altered by ROS, in particular DNA (e.g. mutations, base modifications), proteins (formation of disulfide bridges etc.), lipids (lipid peroxidation), and polysaccharides (depolymerisation). Type and severity of the damage and cellular responses to it, including adaptive enzyme induc­ tion, determine the outcome in terms of cellular dysfunction or death. Many human disorders are thought to be associated with oxidative stress. ROS seem to play a pre­ dominant role, for instance, in radiation effects, damage by oxidant chemicals (many poisons and chemotherapeutic drugs), lung lesions due to hyperbaric oxygen, and chronic deficiencies of selenium and vitamin E. Oxidative stress is also thought to be important in other diseases and processes, e.g. in ischemia-reperfusion damage, central nervous system injury and stroke, severe chronic inflammatory disorders (for example rheumatoid arthritis), the development of arterial atherosclerosis, cancero-genesis, and ageing.