Mitochondrial damage mediates genotoxicity of arsenic in mammalian cells.
Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. For decades, arsenic was considered a nongenotoxic carcinogen. Using the highly sensitive A(L) mutation assay, we previously showed that arsenic is, indeed, a potent gene and chromosomal mutagen and that its effects are mediated through the induction of reactive oxygen species. However, the origin of these radicals and the pathways involved are not known. Here we show that mitochondrial damage plays a crucial role in arsenic mutagenicity. Treatment of enucleated cells with arsenic followed by rescue fusion with karyoplasts from controls resulted in significant mutant induction. In contrast, treatment of mitochondrial DNA-depleted (rho(0)) cells produced few or no mutations. Mitochondrial damage can lead to the release of superoxide anions, which then react with nitric oxide to produce the highly reactive peroxynitrites. The mutagenic damage was dampened by the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine. These data illustrate that mitochondria are a primary target in arsenic-induced genotoxic response and that a better understanding of the mutagenic/carcinogenic mechanism of arsenic should provide a basis for better interventional approach in both treatment and prevention of arsenic-induced cancer.
Liu
Su-Xian
SX
Center for Radiological Research, Department of Neurology, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Davidson
Mercy M
MM
Tang
Xiuwei
X
Walker
Winsome F
WF
Athar
Mohammad
M
Ivanov
Vladimir
V
Hei
Tom K
TK
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D016466:CHO Cells; D006224:Cricetinae; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006822:Hybrid Cells; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009152:Mutagenicity Tests; D030421:Peroxynitrous Acid / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D018053:Arsenites; D004272:DNA, Mitochondrial; D011506:Proteins; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C017947:sodium arsenite