%0 Journal Article %A JOHN E. BIAGLOW %A BIRGIT JACOBSON %A CLIVE L. GREENSTOCK %A JAMES RALEIGH %T Effect of Nitrobenzene Derivatives on Electron Transfer in Cellular and Chemical Models %D 1977 %J Molecular Pharmacology %P 269-282 %V 13 %N 2 %X Cellular, microsomal, and pulse radiolysis studies were undertaken to elucidate the involvement of electron-affinic nitrobenzene derivatives in metabolic processes. In aerated cells the presence of nitrobenzenes resulted in either inhibition or stimulation of oxygen utilization. Nitrobenzenes with oxidation-reduction potentials more negative than —0.35 V inhibited oxygen utilization. This inhibition was not entirely due to production of nitroso intermediates. Nitrosobenzene was found to inhibit oxidation more efficiently than the nitro derivatives. However, nitrosobenzene also stimulated oxygen utilization with antimycin A- or KCN-inhibited cells whereas the nitro inhibitors did not. Nitrobenzene derivatives with oxidation-reduction potentials more positive than —0.35 V stimulated cellular oxygen utilization. This stimulated oxygen consumption was enhanced by adding glucose and was suppressed by the removal of endogenous reducing species. Oxygen utilization was also stimulated in antimycin A- and KCN-inhibited cells, suggesting nonmitochondrial electron transfer to oxygen. This nonmitochondrial oxidation was also stimulated in the presence of glucose and inhibited by removal of GSH. With antimycin A- and KCN-inhibited cells, oxygen utilization was accompanied by accumulation of peroxide. The increased cellular oxidation may be due to microsomal nitroreductase, which activates the nitrobenzenes to oxygen-reactive radical intermediates. Purified microsomes, in the presence of nitrobenzenes and NADPH, consumed oxygen and produced peroxide. Catalase and superoxide dismutase inhibited oxygen consumption by preventing the formation of superoxide radical and peroxide. These results suggest that NADPH may be oxidized by superoxide radical or by the hydroxyl radical, which is produced by the reaction known to occur between O2 and H2O2. Pulse radiolysis studies were initiated in an attempt to determine the mechanism of oxygen stimulation and inhibition. All nitrobenzenes were found to accept electrons from various donor radicals, including the radical intermediate NAD[unknown]. The resultant nitrobenzene radical anions were extremely reactive toward molecular oxygen. In the absence of oxygen the nitrobenzene radical anions were found to dismutate to the original nitro and a nitroso intermediate. This diffusion-controlled reaction was extremely rapid, with a rate constant much larger than the constant for nitrobenzene radical anion reaction with oxygen. The significance of the results with respect to relating the oxidation-reduction potential of the nitrobenzenes to (a) radiosensitization by inhibition of oxygen utilization, (b) choice of drug for chemotherapy of hypoxic-anoxic tumor cells, and (c) potential mutagenic or carcinogenic properties is discussed. ACKNOWLEDGMENTS We thank Dr. Marie Varnes and Dr. Oddvar F. Nygaard of Case Western Reserve University and Dr. Ronald P. Mason of the Clinical Pharmacology Section, Veterans Administration Hospital, Minneapolis, for their critical reviews of the manuscript. %U https://molpharm.aspetjournals.org/content/molpharm/13/2/269.full.pdf