FREE RADICAL METABOLITIES OF TOXIC CHEMICALS

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The objective of this study is to determine the role played by free radicals in the reductive and oxidative metabolism of xenobiotics. The anaerobic incubation of almost all nitroaromatic xenobiotics, e.g., nitrobenzene, by the microsomal, mitochondrial, or cytosolic fractions of rat liver in the presence of either NADH or NADPH, leads to a multiple-line electron spin resonance (ESR) spectrum characteristic of the nitro anion free radical. Halogen-substituted nitro compounds are radiosensitizers and are among the most toxic nitro compounds. Loss of halide by the nitroaromatic anion forms a very reactive carbon-centered free radical, detected by spin trapping, which reacts with cellular macromolecules. The irreversible binding of these nitro compounds to DNA, protein, etc. may be inhibited by spin traps. Free radical formation by hepatic microsomal cytochrome P-450 reduction of gentian violet, SO2, CC14 and O2 has also been investigated. Investigations of the prostaglandin hydroperoxidase and a model enzyme system, horseradish peroxidase, have demonstrated the enzymatic formation of free radical metabolites by oxidation. ESR, on a millisecond time scale, has revealed the formation of a transient phenoxyl radical in the reaction of acetaminophen with horseradish peroxidase/H2O2 and bovine lactoperoxidase/H2O2. The short-lived radical is clearly distinguished from the persistent paramagnetic melanin polymers that are generated by prolonged incubation of acetaminophen in the presence of oxidizing enzymes. Sulfur-centered free radicals have been detected when cysteine was incubated with horseradish peroxidase and H2O2. Reduced glutathione (GSH) was also oxidized to a sulfur-centered radical (GS.) by horseradish peroxidase and H2O2. Since cysteine and glutathione play an important role in the structure and function of sulfhydryl-containing proteins, these oxidation reactions may modulate the biological function of these compounds.