title: Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides.
abstract: The U.S. National Toxicology Program has shown clear evidence of carcinogenicity of nickel subsulfide (Ni(3)S(2)) and some evidence of carcinogenicity of NiO (green) in rats. In the present study, DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. In cultured HeLa cells, Ni(3)S(2) induced a significant increase in 8-hydroxydeoxyguanosine (8-OH-dG) formation, whereas NiO (black), NiO (green), and NiSO(4) did not. On the other hand, in rats, intratracheal instillation of all these nickel compounds significantly increased 8-OH-dG content in the lungs. The disparities in DNA damage between cultured cells and animals could be accounted for by two different mechanisms for nickel-induced oxidative DNA damage in lungs of rats. One is direct oxidative DNA damage: Ni(II) enters the cells and then reacts with endogenous and/or nickel sulfide-produced hydrogen peroxide (H(2)O(2)) to give reactive oxygen species that cause DNA damage. This mechanism is supported by oxidative damage to isolated DNA treated with Ni(II) and H(2)O(2). The other mechanism is indirect oxidative DNA damage due to inflammation. This double mechanism for DNA damage may explain the relatively high carcinogenic risk associated with Ni(3)S(2).
authors.affiliation: Department of Hygiene, Mie University School of Medicine, Mie 514-8507, Japan. kawanisi@doc.medic.mie-u.ac.jp
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
authors.forename: Sumiko
authors.initials: S
authors.lastname: Inoue
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Nishino
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000009:adverse effects* / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007249:Inflammation / Q000503:physiopathology; D008168:Lung / Q000166:cytology; D009532:Nickel / Q000009:adverse effects* / Q000494:pharmacology; D016877:Oxidants / Q000737:chemistry; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species; D018570:Risk Assessment
chemical_list: D002273:Carcinogens; D016877:Oxidants; D017382:Reactive Oxygen Species; D009532:Nickel; D006861:Hydrogen Peroxide; C028007:nickel monoxide; C017557:nickel subsulfide