Siim B G, Wilson W R
Department of Pathology, University of Auckland, New Zealand.
Biochem Pharmacol. 1995 Jun 29;50(1):75-82. doi: 10.1016/0006-2952(95)00112-d.
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).
带有4-烷基氨基取代基的硝基喹啉生物还原药物在哺乳动物细胞中经历单电子还原，由于需氧培养中硝基自由基阴离子的氧化，导致无效的氧化还原循环，并且在无氧条件下最终还原为相应的胺。测定了17种硝基喹啉在氰化物处理的AA8细胞培养物中因氧化还原循环引起的药物诱导耗氧率（R）。在pH 7时，log R与单电子还原电位（E(7)1）呈线性关系，斜率为7.1 V-1，但不包括硝基邻位带有取代基的化合物。相对于E(7)1，后者的耗氧率异常低，这表明此类化合物与硝基还原酶活性位点的相互作用受到空间位阻。通过一个简单的动力学模型可以很好地预测R的绝对值（以及观察到的对E(7)1的依赖性），该模型使用缺氧条件下胺的净硝基还原速率作为需氧细胞中单电子还原速率的度量。这表明4-烷基氨基硝基喹啉在需氧细胞中高效地发生氧化还原循环，这表明细胞中硝基自由基阴离子除了与氧反应（或在缺氧条件下自发歧化）外，没有其他数量上显著的归宿。
