Free radical mediated cell toxicity by redox cycling chemicals

Free radical formation has been implicated in the toxicity of a wide range of xenobiotics. In recent years, particular interest has been paid to compounds which can undergo a one electron reduction to form a radical species which can then react with oxygen forming superoxide (O2.-) and regenerating the parent molecule. This process, which is called redox cycling, leads to a disproportionate consumption of O2 and cellular reducing equivalents and the formation of active oxygen species, ultimately causing oxidative stress. It has been proposed that cell death results from a loss in control of Ca2+ homeostasis caused by thiol oxidation at critical enzyme sites. Physical properties of redox cycling compounds such as their one electron reduction potentials are important in determining their rate of reduction by cellular reductases and the reactivity of the radicals so formed with oxygen and other molecules. Although redox cycling of many compounds can be clearly demonstrated in vitro, the unequivocal demonstration of this process in vivo and its involvement in in vivo toxicities remains a challenging area for future research.