OXIDATIVE STRESS CAUSED BY GLYCATION OF CU,ZN-SUPEROXIDE DISMUTASE AND ITS EFFECTS ON INTRACELLULAR COMPONENTS

It is now evident that the redox state of the cell is a pivotal determ inant of the fate of cells. Extensive production of reactive oxygen sp ecies (ROI) causes necrotic cell death. Even transient or localized pr oduction of ROI may mediate a signal for apoptotic cell death, whereas small amounts of ROI function as an intracellular messenger of some g rowth stimulants. Accumulating evidence supports the concept that decr eases in Cu,Zn-superoxide dismutase (SOD) activity causes apoptotic ce ll death in neuronal cells. Our data using mutant Cu,Zn-SOD related to familial amyotrophic lateral sclerosis (FALS) suggest that glycation itself and ROI produced from the glycated proteins are involved in man y diseases, including diabetic complications. Glycation of important c ellular components, including lipid, DNA and proteins, induces dysfunc tion of these components. Mutant proteins in patients with various her editary diseases would be destabilized by the glycation reaction, as s hown in the case of mutant Cu,Zn-SODs, thereby hyperglycaemic conditio ns would trigger the onset of some hereditary diseases such as FALS an d Alzheimer's disease. Glycation, particularly of antioxidative enzyme s, would enhance production of ROI, resulting in oxidative damage to t he cells.