title: Mechanisms of oxidative DNA damage induced by carcinogenic arylamines.
abstract: Most arylamines are pro-carcinogens, and require metabolic activation to yield ultimate carcinogen metabolites. O-Acetylation of the N-hydroxy form of an arylamine yields an acetoxyarylamine, which can form a highly reactive arylnitrenium ion, the ultimate metabolite responsible for DNA adduct formation. However, we demonstrate here that the N-hydroxy and nitroso forms of arylamines can also induce DNA damage, including 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) lesions, via reactive oxygen species formation. The N-hydroxy and nitroso derivatives of carcinogenic arylamines may contribute to the carcinogenic process through H2O2 formation. N-Hydroxy derivatives induce metal-mediated DNA damage, with remarkable enhancement by NADH. Nitroso derivatives induce NADH-dependent DNA damage in the presence of metal ions. Hydroxy derivatives of arylamines formed by enzymatic hydroxylation or as o- or p-aminophenols can also induce DNA damage in the presence of metal ions. The autoxidation of o-phenylenediamine and several arylamine metabolites is accelerated in the presence of SOD or manganese, resulting in the enhancement of metal-mediated DNA damage. The oxidative DNA damage induced by arylamine compounds may participate in chemical carcinogenesis, in addition to DNA adduct formation.
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan. mmurata@doc.medic.mie-u.ac.jp
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000611:Aminobiphenyl Compounds / Q000009:adverse effects; D000818:Animals; D001560:Benzidines / Q000009:adverse effects; D002273:Carcinogens / Q000378:metabolism / Q000494:pharmacology*; D018736:DNA Adducts; D004249:DNA Damage; D003849:Deoxyguanosine / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced*; D010084:Oxidation-Reduction
chemical_list: D000611:Aminobiphenyl Compounds; D001560:Benzidines; D002273:Carcinogens; D018736:DNA Adducts; C006757:4-biphenylamine; C029876:benzidine; C014593:N-hydroxy-4-aminobiphenyl; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine