title: Effect of soluble and particulate nickel compounds on the formation and repair of stable benzo[a]pyrene DNA adducts in human lung cells.
abstract: Nickel compounds are well-known human carcinogens, but the underlying mechanisms are still not fully understood. Even though only weakly mutagenic, nickel chloride has been shown previously to impair the repair of UV-induced DNA damage as well as oxidative DNA damage. However, the carcinogenic potential depends largely on solubility, with poorly water-soluble nickel subsulfide and nickel oxide being strong carcinogens. Within the present study we investigated the effects of particulate black NiO and soluble NiCl(2) on the induction and removal of stable DNA adducts formed by benzo[a]pyrene (B[a]P) measured by a highly sensitive high performance liquid chromatography (HPLC)/fluorescence assay. With respect to adduct formation, NiO but not NiCl(2) reduced the generation of DNA lesions by approximately 30%. Regarding their repair, in the absence of nickel compounds, most lesions were removed within 24 h; nevertheless, between 20 and 35% of induced adducts remained even 48 h after treatment. NiCl(2) and NiO reduced the removal of adducts in a dose-dependent manner. Thus, 100 microM NiCl(2) led to approximately 80% residual repair capacity; after 500 microM the repair was reduced to approximately 36%. Also, even at the completely non-cytotoxic concentration of 0.5 microg/cm(2) black NiO, lesion removal was reduced to approximately 35% of control and to 15% at 2.0 microg/cm(2). Furthermore, both nickel compounds increased the benzo[a]pyrene-7,8-diol 9,10-epoxide (BPDE)-induced cytotoxicity. Taken together, our results indicate that the nucleotide excision repair pathway is affected in general by water-soluble and particulate nickel compounds and provide further evidence that DNA repair inhibition may be one predominant mechanism in nickel-induced carcinogenicity.
authors.affiliation: Institut für Lebensmittelchemie und Toxikologie, Universität Karlsruhe, D-76128 Karlsruhe, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schwerdtle
authors.forename: Albrecht
authors.initials: A
authors.lastname: Seidel
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartwig
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism* / Q000633:toxicity; D001580:Benzopyrenes / Q000378:metabolism; D002138:Calibration; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009532:Nickel / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012995:Solubility; D013234:Stem Cells / Q000187:drug effects
chemical_list: D001580:Benzopyrenes; D018736:DNA Adducts; C121255:anti-benzo(a)pyrene-dA adduct; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C022838:nickel chloride; D009532:Nickel; C028007:nickel monoxide