Site-specific DNA damage and 8-hydroxydeoxyguanosine formation by hydroxylamine and 4-hydroxyaminoquinoline 1-oxide in the presence of Cu(II): role of active oxygen species.
Mutagenic hydroxylamine (NH2OH) and 4-hydroxyamino-quinoline 1-oxide (4-HAQO), a carcinogenic metabolite of 4-nitroquinoline 1-oxide (4-NQO), cleaved isolated DNA in the presence of Cu(II), but not in the presence of Mn(II), Mn(III), Fe(II) or Fe(III). The Cu(II)-mediated DNA damage by NH2OH was inhibited by catalase and bathocuproine, a Cu(I)-specific chelator, but not by scavengers of hydroxyl free radical. With the Cu(II)-mediated DNA damage by 4-HAQO, similar scavenger effects were observed. It is suggested that free .OH is not the main active species causing the DNA damage in both the cases. The predominant cleavage sites were thymine residues, especially the thymine residue of 5'-GTC-3' sequence. Since the cleavage pattern was similar to that induced by Cu(I) plus H2O2 but not to that induced by Cu(II) plus H2O2, it is speculated that the copper-oxygen complex derived from the reaction of H2O2 with Cu(I) participates in the DNA damage. 8-Hydroxydeoxyguanosine (8-OH-dG) residues were efficiently formed in calf thymus DNA treated with NH2OH plus Cu(II) or 4-HAQO plus Cu(II). The role of Cu(II)-mediated DNA damage and 8-OH-dG formation in the genotoxicity of NH2OH, 4-HAQO and 4-NQO is discussed.
Yamamoto
K
K
Department of Public Health, Faculty of Medicine, Kyoto University, Japan.
Inoue
S
S
Kawanishi
S
S
D015108:4-Hydroxyaminoquinoline-1-oxide / Q000633:toxicity*; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002417:Cattle; D003300:Copper / Q000737:chemistry*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D016166:Free Radical Scavengers; D019811:Hydroxylamine; D006898:Hydroxylamines / Q000633:toxicity*; D007501:Iron / Q000737:chemistry; D008345:Manganese / Q000737:chemistry; D009153:Mutagens / Q000633:toxicity; D017382:Reactive Oxygen Species
D016166:Free Radical Scavengers; D006898:Hydroxylamines; D009153:Mutagens; D017382:Reactive Oxygen Species; D019811:Hydroxylamine; D008345:Manganese; D015108:4-Hydroxyaminoquinoline-1-oxide; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D007501:Iron; D003849:Deoxyguanosine