The superoxide production mediated by the redox cycling of xenobiotics in rat brain microsomes is dependent on their reduction potential

Several exogenous molecules undergo enzymatic one-electron reduction leading to radicals which can rapidly react with molecular oxygen to form superoxide anions. We have previously shown that under aerobic conditions a significant superoxide anion production occurred during the NADPH-dependent one-electron reduction of some drugs and xenobiotics by rat brain preparations. We report here for several compounds a fairly good correlation between the reduction potentials (Epc vs. SCE) which ranged between - 230 and - 700 mV in aqueous medium (pH 7.4) or between - 700 mV and - 1100 mV in the aprotic solvent N,N-dimethylformamide, and the rate of superoxide anion production during their metabolism by rat brain microsomes. The data obtained suggest that the redox potential of most of the molecules assayed was related to their ability to undergo one-electron reduction mediated by flavoenzymes in the rat brain. The main range of reduction potentials corresponding to a large superoxide anion production suggests that the redox cycling of these chemicals was mediated by NADPH-cytochrome P-450 reductase. Therefore the measurement of reduction potentials of drugs and xenobiotics able to reach the brain, and chemically related to quinones, nitroaromatics, nitroheterocyclics and iminiums, may provide information both on their electron affinity and the possibility of one-electron transfer in vivo, and thus on their possible neurotoxicity due to the production of oxygenated free radicals.