Šarlauskas Jonas, Nemeikaitė-Čėnienė Aušra, Misevičienė Lina, Krikštopaitis Kastis, Anusevičius Žilvinas, Čėnas Narimantas
Institute of Biochemistry of Vilnius University, Vilnius, Lithuania.
Acta Biochim Pol. 2013;60(2):227-31. Epub 2013 Jun 13.
In order to characterize the possible mechanism(s) of cytotoxicity of a neuroleptic agent 6,7-dinitrodihydroquinoxaline-2,3-dione (DNQX) we examined the redox properties of DNQX, and its mononitro- (NQX) and denitro- (QX) derivatives. The irreversible electrochemical reduction of the nitro groups of DNQX was characterized by the reduction peak potentials (Ep,7) of -0.43 V and -0.72 V vs. Ag/AgCl at pH 7.0, whereas NQX was reduced at Ep,7 = -0.67 V. The reactivities of DNQX and NQX towards the single-electron transferring enzymes NADPH:cytochrome P-450 reductase and NADPH:adrenodoxin reductase/adrenodoxin complex were similar to those of model nitrobenzenes with the single-electron reduction potential (E¹₇) values of -0.29 V - -0.42 V. DNQX and NQX also acted as substrates for two-electron transferring mammalian NAD(P)H:quinone oxidoreductase (DT-diaphorase). The cytotoxicity of DNQX in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK) was prevented by antioxidants and an inhibitor of NQO1, dicoumarol, and was enhanced by the prooxidant alkylating agent 1,3-bis(2-chloromethyl)-1-nitrosourea. A comparison with model nitrobenzene compounds shows that the cytotoxicity of DNQX and NQX reasonably agrees with the ease of their electrochemical reduction, and/or their reactivities towards the used enzymatic single-electron reducing systems. Thus, our data imply that the cytotoxicity of DNQX in FLK cells is exerted mainly through oxidative stress.
为了表征抗精神病药物6,7 - 二硝基二氢喹喔啉 - 2,3 - 二酮（DNQX）的细胞毒性可能机制，我们研究了DNQX及其单硝基 - （NQX）和脱硝基 - （QX）衍生物的氧化还原性质。DNQX硝基的不可逆电化学还原在pH 7.0时相对于Ag/AgCl的还原峰电位（Ep,7）为 -0.43 V和 -0.72 V，而NQX在Ep,7 = -0.67 V时被还原。DNQX和NQX对单电子转移酶NADPH：细胞色素P - 450还原酶以及NADPH：肾上腺皮质铁氧化还原蛋白还原酶/肾上腺皮质铁氧化还原蛋白复合物的反应性与单电子还原电位（E¹₇）值为 -0.29 V - -0.42 V的模型硝基苯相似。DNQX和NQX还作为双电子转移的哺乳动物NAD(P)H：醌氧化还原酶（DT - 黄递酶）的底物。抗氧化剂和NQO1抑制剂双香豆素可预防DNQX在牛白血病病毒转化的羔羊肾成纤维细胞（FLK系）中的细胞毒性，而促氧化剂烷基化剂1,3 - 双（2 - 氯甲基） - 1 - 亚硝基脲可增强其细胞毒性。与模型硝基苯化合物的比较表明，DNQX和NQX的细胞毒性与其电化学还原的难易程度和/或它们对所用酶促单电子还原系统的反应性合理相符。因此，我们的数据表明，DNQX在FLK细胞中的细胞毒性主要通过氧化应激发挥作用。
