Free radicals in toxicology.

Free radicals are recognized more and more frequently as being involved in the mechanism of toxicity of chemicals. In some cases, the organic radicals are involved, but often oxygen radicals result from redox cycling chemicals. Free radicals are usually very reactive, which, in addition to causing toxicities, can make them difficult to detect. Electron spin resonance (ESR) techniques are frequently used, but generally the radicals must be trapped to form a more stable radical for detection. Quantitation is therefore often very difficult. Free radicals of many xenobiotics are formed during their metabolism by enzymes such as cytochrome P450 or peroxidases. In some cases, chemicals can redox cycle using reductases, such as cytochrome P450 reductase, which can catalyze one-electron reductions. Some redox cycling xenobiotics reduce molecular oxygen by one electron to generate superoxide. Superoxide can cause toxicities against which superoxide dismutase is protective. However, in the presence of transition metals such as iron, superoxide can generate the very reactive hydroxyl radical by the iron-catalyzed Haber-Weiss reaction. Iron is therefore normally tightly controlled by transport and storage proteins. Chemicals that can release iron from these proteins can be very toxic, causing lipid, protein, and nucleic acid oxidation. The oxidation of these species, such as a low-density lipoprotein, is generally protected by a complex antioxidant system involving glutathione and glutathione peroxidase, vitamin E, ascorbic acid, etc.