Molecular Pharmacology, Vol 20, 669-673, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

The Kinetics of the Aerobic Reduction of Nitrofurantoin by NADPH-Cytochrome P-450 (c) Reductase

¹ Veterans Administration Medical Center, Minneapolis, Minnesota 55417, and Departments of Medicine and Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

In vivo studies have indicated that mammalian organisms can reduce nitro aromatic compounds. This reduction occurs primarily in liver. On the other hand, nitro reductase activity is not observed in vitro for liver preparations under the aerobic conditions found in mammalian tissues. Studies from our laboratory suggest that this inhibition is due to the rapid reoxidation of the first reduction product, the nitro aromatic anion radical. We now find that physiological concentrations of detergent-solubilized microsomal NADPH-cytochrome P-450 (c) reductase can reduce nitrofurantoin aerobically. The rate is about 14% of the anaerobic rate of metabolism. This reduction is second-order in both substrate and enzyme, in agreement with the concept that it proceeds through the initial formation of the 5-nitrofuran anion radical. This radical then disproportionates to form the nitroso and reform the parent drug. These data indicate that the rate of disproportionation of the anion radical is comparable to the rate of reoxidation of the radical by oxygen. Furthermore, since these results demonstrate rapid nitroreduction in an aerobic mammalian system, they lend support to the hypothesis that the nitroaromatic carcinogens and radiosensitizers are metabolically activated in vivo by reduction to their nitroso and hydroxylamine derivatives.

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ACKNOWLEDGMENTS We wish to acknowledge the interest of Dr. R. P. Mason in these studies and the secretarial skills of L. M. Starks.