Arsenite induces oxidative DNA adducts and DNA-protein cross-links in mammalian cells.
Arsenic is generally recognized as a nonmutagenic carcinogen because sodium arsenite induces DNA damage only at very high concentrations. In this study we demonstrate that arsenite concentrations above 0.25 microM induce DNA strand breaks in both human leukemia cells and Chinese hamster ovary cells. Therefore, DNA damage may be involved in arsenic-induced carcinogenesis. Formamidopyrimidine-DNA glycosylase and proteinase K greatly increased DNA strand breaks in arsenite-treated cells, providing evidence that a large portion of arsenite-induced DNA strand breaks come from excision of oxidative DNA adducts and DNA-protein cross-links. Because DNA strand breaks appear only temporarily during excision repair, the level of detectable DNA strand breaks will be low at any given time point. For this reason many previous studies have only detected low levels of DNA strand breaks. We also show that catalase, and inhibitors of calcium, nitric oxide synthase, superoxide dismutase, and myeloperoxidase, could modulate arsenite-induced DNA damage. We conclude that arsenite induces DNA adducts through calcium-mediated production of peroxynitrite, hypochlorous acid, and hydroxyl radicals.
Wang
T S
TS
Department of Life Science, Chung Shan Medical and Dental College, Taichung, Taiwan.
Hsu
T Y
TY
Chung
C H
CH
Wang
A S
AS
Bau
D T
DT
Jan
K Y
KY
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003432:Cross-Linking Reagents; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D043382:DNA-Formamidopyrimidine Glycosylase; D019286:Endopeptidase K / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*
D018053:Arsenites; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D005609:Free Radicals; D017670:Sodium Compounds; C017947:sodium arsenite; D004247:DNA; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D019286:Endopeptidase K