title: Inorganic arsenic compounds cause oxidative damage to DNA and protein by inducing ROS and RNS generation in human keratinocytes.
abstract: Arsenic is a naturally occurring element that is present in food, soil, and water. Inorganic arsenic can accumulate in human skin and is associated with increased risk of skin cancer. Oxidative stress due to arsenic exposure is proposed as one potential mode of carcinogenic action. The purpose of this study is to investigate the specific reactive oxygen and nitrogen species that are responsible for the arsenic-induced oxidative damage to DNA and protein. Our results demonstrated that exposure of human keratinocytes to trivalent arsenite caused the generation of 8-hydroxyl-2'-deoxyguanine (8-OHdG) and 3-nitrotyrosine (3-NT) in a concentration- and time-dependent manner. Pentavalent arsenate had similar effects, but to a significantly less extent. The observed oxidative damage can be suppressed by pre-treating cells with specific antioxidants. Furthermore, we found that pre-treating cells with Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), or with 5,10,15,20-tetrakis (N-methyl-4'-pyridyl) porphinato iron (III) chloride (FeTMPyP), a decomposition catalyst of peroxynitrite, suppressed the generation of both 8-OHdG and 3-NT, which indicated that peroxynitrite, a product of the reaction of nitric oxide and superoxide, played an important role in arsenic-induced oxidative damage to both DNA and protein. These findings highlight the involvement of peroxynitrite in the molecular mechanism underlying arsenic-induced human skin carcinogenesis.
authors.affiliation: Program of Toxicology, College of Pharmacy, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D001149:Arsenates / Q000633:toxicity*; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D030421:Peroxynitrous Acid / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000096:biosynthesis / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017670:Sodium Compounds / Q000633:toxicity*; D013482:Superoxide Dismutase; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism
chemical_list: C492721:5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato-iron(III); D001149:Arsenates; D018053:Arsenites; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C017947:sodium arsenite; C009277:sodium arsenate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D003849:Deoxyguanosine; D019331:NG-Nitroarginine Methyl Ester