Efficient redox cycling of nitroquinoline bioreductive drugs due to aerobic nitroreduction in Chinese hamster cells.

Nitroquinoline bioreductive drugs with 4-alkylamino substituents undergo one-electron reduction in mammalian cells, resulting in futile redox cycling due to oxidation of the nitro radical anion in aerobic cultures, and eventual reduction to the corresponding amines in the absence of oxygen. Rates of drug-induced oxygen consumption (R) due to redox cycling in cyanide-treated AA8 cell cultures were determined for 17 nitroquinolines. There was a linear dependence of log R on the one-electron reduction potential at pH 7 (E(7)1 with a slope of 7.1 V-1, excluding compounds with substituents ortho to the nitro group. The latter had anomalously low rates of oxygen consumption relative to E(7)1, suggesting that interaction with the active site of nitroreductases is impeded sterically for such compounds. Absolute values of R (and the observed E(7)1 dependence) were well predicted by a simple kinetic model that used rates of net nitroreduction to the amines under anoxia as a measure of the rates of one-electron reduction in aerobic cells. This indicates that redox cycling of 4-alkylaminonitroquinolines occurs at high efficiency in aerobic cells, suggesting that there are no quantitatively significant fates of nitro radical anions in cells other than their reaction with oxygen (or their spontaneous disproportionation under hypoxia).