Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite.
Arsenic is recognized to be a nonmutagenic carcinogen because it induces DNA damage only at very high concentrations. However, many more DNA strand breaks could be detected by digesting the DNA of arsenite-treated cells with endonuclease III, formamidopyrimidine-DNA glycosylase, and proteinase K. By doing so, arsenite could be shown to induce DNA damage in human cells within a pathologically meaningful concentration range. Oxidized guanine products were detected in all arsenite-treated human cells examined. DNA-protein cross-links were also detected in arsenite-treated NB4 and HL60 cells. In human umbilical vein endothelial cells, the induction of oxidized guanine products by arsenite was sensitive to inhibitors of nitric oxide (NO) synthase but not to oxidant modulators, whereas the opposite result was obtained in vascular smooth muscle cells. On the other hand, the arsenite-induced oxidized guanine products and DNA-protein cross-links in NB4 and HL60 cells were sensitive to modulators of calcium, NO synthase, oxidant, and myeloperoxidase. Therefore, although oxidized guanine products were detected in all the human cells treated with arsenite, the pathways could be different in different cell types. Because the sensitivity and the mechanism of arsenic intoxication are cell specific, it is important that target tissues and target cells are used for investigations. It is also important that pathologically or pharmacologically meaningful concentrations of arsenic are used. This is because in most cases we are dealing with the chronic effect rather than acute toxicity.
Bau
Da-Tian
DT
Institute of Zoology, Academia Sinica, Taipei 11529, Taiwan, Republic of China.
Wang
Tsu-Shing
TS
Chung
Chiao-Hui
CH
Wang
Alexander S S
AS
Wang
Alexander S S
AS
Jan
Kun-Yan
KY
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D016466:CHO Cells; D018929:Cell Culture Techniques; D006224:Cricetinae; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts; D006147:Guanine / Q000737:chemistry; D006801:Humans; D006997:Hypochlorous Acid / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000494:pharmacology; D018384:Oxidative Stress; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000009:adverse effects; D013723:Teratogens / Q000633:toxicity*
D018053:Arsenites; D018736:DNA Adducts; D017382:Reactive Oxygen Species; D013723:Teratogens; D006147:Guanine; D006997:Hypochlorous Acid; D004247:DNA; D019001:Nitric Oxide Synthase; C015001:arsenite