title: Nonenzymatic reduction of nitro derivative of a heterocyclic amine IQ by NADH and Cu(II) leads to oxidative DNA damage.
abstract: Nitro derivative (nitro-IQ) of a carcinogenic heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is known to be a potent mutagen as well as IQ, and nitro-IQ is believed to be activated enzymatically by nitroreductase. We investigated nonenzymatic reduction of nitro-IQ by an endogenous reductant NADH and the ability of inducing DNA damage by nitro-IQ. Nitro-IQ caused DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine in the presence of NADH and Cu(II). Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of H2O2 and Cu(I). Nitro-IQ induced DNA cleavage frequently at thymine and cytosine residues in the presence of NADH and Cu(II). UV-vis spectroscopic study showed that no spectral change of Nitro-IQ and NADH was observed in the absence of Cu(II), while rapid spectral change was observed in the presence of Cu(II), suggesting that Cu(II) mediated redox reaction of nitro-IQ and NADH. These results suggest that nitro-IQ can be reduced nonenzymatically by NADH in the presence of Cu(II), and the redox reaction resulted in oxidative DNA damage due to the copper-oxygen complex, derived from the reaction of Cu(I) with H2O2. We conclude that nonenzymatic reduction of nitro-IQ and resulting in oxidative DNA damage can play a role in carcinogenesis of IQ.
authors.affiliation: Department of Hygiene, Mie University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002417:Cattle; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry; D016166:Free Radical Scavengers / Q000737:chemistry; D006801:Humans; D009153:Mutagens / Q000737:chemistry; D009243:NAD / Q000737:chemistry*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010618:Phenanthrolines / Q000737:chemistry; D010761:Phosphorus Radioisotopes; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry / Q000235:genetics; D011804:Quinolines / Q000737:chemistry* / Q000633:toxicity; D013056:Spectrophotometry, Ultraviolet; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics
chemical_list: D016166:Free Radical Scavengers; D009153:Mutagens; D010618:Phenanthrolines; D010761:Phosphorus Radioisotopes; D011804:Quinolines; D016159:Tumor Suppressor Protein p53; D009243:NAD; C071417:2-nitro-3-methylimidazo(4,5-f)quinoline; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C002478:bathocuproine; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D003849:Deoxyguanosine