title: Redox properties and prooxidant cytotoxicity of a neuroleptic agent 6,7-dinitrodihydroquinoxaline-2,3-dione (DNQX).
abstract: 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.
authors.affiliation: Institute of Biochemistry of Vilnius University, Vilnius, Lithuania.
authors.forename: Jonas
authors.initials: J
authors.lastname: Šarlauskas
authors.forename: Aušra
authors.initials: A
authors.lastname: Nemeikaitė-Čėnienė
authors.forename: Lina
authors.initials: L
authors.lastname: Misevičienė
authors.forename: Kastis
authors.initials: K
authors.lastname: Krikštopaitis
authors.forename: Žilvinas
authors.initials: Ž
authors.lastname: Anusevičius
authors.forename: Narimantas
authors.initials: N
authors.lastname: Čėnas
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D001728:Dicumarol / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects; D009578:Nitrobenzenes / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C583951:6-nitrodihydroquinoxaline-2,3-dione; D000975:Antioxidants; D009578:Nitrobenzenes; D011810:Quinoxalines; C056723:FG 9041; D001728:Dicumarol; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone)