Drug-Induced Protein Free Radical Formation Is Attenuated by Unsaturated Fatty Acids by Scavenging Drug-Derived Phenyl Radical Metabolites

Aromatic amine drugs like aminoglutethimide (AG) and related congeners have been shown to produce phenyl radicals through metabolism by myeloperoxidase (MPO)/H2O2, which has been proposed to play a role in drug-induced agranulocytosis. AG has also been shown to induce MPO protein radical formation, but the ultimate fate of these metabolically generated phenyl radicals is still unknown. We tested the reactivity of linoleic acid (LA) and GSH with aniline-based compounds in the presence of horseradish peroxidase (HRP)/H2O2 by measuring oxygen consumption. We found a qualitative correlation between drugs or xenobiotics that formed phenyl radical metabolites with the cooxidation of LA. Most compounds that reacted with LA did not react with GSH. Furthermore, an AG-derived phenyl radical was detected by EPR spin-trapping with MNP (2-methyl-2-nitrosopropane), in a reaction containing AG and HRP/H2O2; these spectra were attenuated in the presence of LA and docosahexaenoic acid (DHA) indicating that phenyl radical ...