Siim B G, Atwell G J, Wilson W R
Department of Pathology, University of Auckland School of Medicine, New Zealand.
Biochem Pharmacol. 1994 Oct 18;48(8):1593-604. doi: 10.1016/0006-2952(94)90204-6.
The 4-alkylamino-5-nitroquinolines (5NQs) are a new series of bioreductive drugs that exhibit varying degrees of selective toxicity (up to 60-fold) under hypoxic conditions in cell culture. This study tested the hypothesis that differences in hypoxia-selective cytotoxicity in this series reflect differences in the efficiency with which oxygen inhibits metabolic reduction. The products of reduction of six 5NQs were characterized and rates of reduction compared in aerobic and hypoxic AA8 cells. The major stable products of both radiolytic and metabolic reduction under anoxic conditions were the corresponding amines, which were not responsible for the toxicity of the parent nitro compounds. Metabolism of each compound was inhibited completely in aerobic cells, indicating that differences in hypoxia-selective toxicity in this series are not due to variations in efficiency as substrates for oxygen-insensitive nitro reduction. Rates of hypoxic metabolism correlated broadly with hypoxia-selective cytotoxicity; the 5NQ derivatives with high rates of hypoxic metabolism had good hypoxia-selective cytotoxicity, whereas the compounds with low rates of reduction (the 3,6-dimethyl and 8-methylamino compounds; 3,6diMe-5NQ and 8NHMe-5NQ) were non-selective. Low rates of drug-induced oxygen consumption by 3,6-diMe-5NQ and 8NHMe-5NQ in respiration-inhibited cells confirmed that these compounds are poor substrates for enzymatic nitro reduction. While there was an overall correlation between one-electron reduction potential at pH 7 (E1(7)) and rate of metabolic reduction, the relatively high E1(7) of 3,6diMe-5NQ (-367 mV) indicates that rates of reduction, and hypoxic selectivity of cytotoxicity, cannot be predicted from reduction potential alone. 3,6diMe-5NQ and 8NHMe-5NQ are cytotoxic through a non-bioreductive mechanism, the variable contribution of which may underlie the differences in hypoxia-selective cytotoxicity within this series of bioreductive drugs.
4-烷基氨基-5-硝基喹啉（5NQs）是一类新型的生物还原药物，在细胞培养的低氧条件下表现出不同程度的选择性毒性（高达60倍）。本研究检验了这样一个假设：该系列中低氧选择性细胞毒性的差异反映了氧气抑制代谢还原效率的差异。对六种5NQs的还原产物进行了表征，并比较了需氧和低氧AA8细胞中的还原速率。在缺氧条件下，辐射还原和代谢还原的主要稳定产物都是相应的胺，它们与母体硝基化合物的毒性无关。每种化合物的代谢在需氧细胞中被完全抑制，这表明该系列中低氧选择性毒性的差异并非由于作为对氧不敏感的硝基还原底物的效率变化所致。低氧代谢速率与低氧选择性细胞毒性大致相关；低氧代谢速率高的5NQ衍生物具有良好的低氧选择性细胞毒性，而还原速率低的化合物（3,6-二甲基和8-甲基氨基化合物；3,6-二甲基-5NQ和8-NHMe-5NQ）则无选择性。在呼吸抑制细胞中，3,6-二甲基-5NQ和8-NHMe-5NQ引起的药物诱导耗氧率较低，证实这些化合物是酶促硝基还原的不良底物。虽然pH 7时的单电子还原电位（E1(7)）与代谢还原速率之间存在总体相关性，但3,6-二甲基-5NQ相对较高的E1(7)（-367 mV）表明，还原速率和细胞毒性的低氧选择性不能仅从还原电位来预测。3,6-二甲基-5NQ和8-NHMe-5NQ通过非生物还原机制产生细胞毒性，其可变作用可能是该系列生物还原药物中低氧选择性细胞毒性差异的基础。
