title: The role of metals in site-specific DNA damage with reference to carcinogenesis.
abstract: We reviewed the mechanism of oxidative DNA damage with reference to metal carcinogenesis and metal-mediated chemical carcinogenesis. On the basis of the finding that chromium (VI) induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2), we proposed the hypothesis that endogenous reactive oxygen species play a role in metal carcinogenesis. Since then, we have reported that various metal compounds, such as cobalt, nickel, and ferric nitrilotriacetate, directly cause site-specific DNA damage in the presence of H2O2. We also found that carcinogenic metals could cause DNA damage through indirect mechanisms. Certain nickel compounds induced oxidative DNA damage in rat lungs through inflammation. Endogenous metals, copper and iron, catalyzed ROS generation from various organic carcinogens, resulting in oxidative DNA damage. Polynuclear compounds, such as 4-aminobiphenyl and heterocyclic amines, appear to induce cancer mainly through DNA adduct formation, although their N-hydroxy and nitroso metabolites can also cause oxidative DNA damage. On the other hand, mononuclear compounds, such as benzene metabolites, caffeic acid, and o-toluidine, should express their carcionogenicity through oxidative DNA damage. Metabolites of certain carcinogens efficiently caused oxidative DNA damage by forming NADH-dependent redox cycles. These findings suggest that metal-mediated oxidative DNA damage plays important roles in chemical carcinogenesis.
authors.affiliation: Department of Hygiene, Mie University School of Medicine, Edobashi, Tsu, Japan. kawanisi@doc.medic.mie-u.ac.jp
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
mesh_terms: D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D005609:Free Radicals; D006801:Humans; D008670:Metals / Q000633:toxicity*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species
chemical_list: D002273:Carcinogens; D005609:Free Radicals; D008670:Metals; D017382:Reactive Oxygen Species; D004247:DNA