Induction of oxyradicals by arsenic: Implication for mechanism of genotoxicity

Abstract

Although arsenic is a well-established human carcinogen, the mechanisms by which it induces cancer remain poorly understood. We previously showed arsenite to be a potent mutagen in humanhamster hybrid (AL) cells, and that it induces predominantly multilocus deletions. We show here by confocal scanning microscopy with the fluorescent probe 5,6-chloromethyl-2,7-dichlorodihydrofluorescein diacetate that arsenite induces, within 5 min after treatment, a dose-dependent increase of up to 3-fold in intracellular oxyradical production. Concurrent treatment of cells with arsenite and the radical scavenger DMSO reduced the fluorescent intensity to control levels. ESR spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-1-hydroxypiperidine (TEMPOL-H) as a probe in conjunction with superoxide dismutase and catalase to quench superoxide anions and hydrogen peroxide, respectively, indicates that arsenite increases the levels of superoxide-driven hydroxyl radicals in these cells. Furthermore, reducing the intracellular levels of nonprotein sulfhydryls (mainly glutathione) in A L cells with buthionine S-R-sulfoximine increases the mutagenic potential of arsenite by more than 5-fold. The data are consistent with our previous results with the radical scavenger DMSO, which reduced the mutagenicity of arsenic in these cells, and provide convincing evidence that reactive oxygen species, particularly hydroxyl radicals, play an important causal role in the genotoxicity of arsenical compounds in mammalian cells.

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

“…Arsenite is widely used to induce oxidative stress (Bernstam & Nriagu, 2000; Liu et al , 2001). Following arsenite removal, cells were extensively washed and then infected with Shigella; infection efficiency was monitored at early, intermediate, and late stages of infection (0.5, 2, and 6 hpi, respectively; Fig 1A) by: (i) fluorescence microscopy, (ii) colony‐forming unit (cfu) assays, and (iii) qRT–PCR.…”

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

“…The mechanism of arsenic carcinogenesis is unresolved. Studies have indicated that arsenic may be genotoxic by generating oxidative stress (Liu et al, 2001b). Alternatively, the National Research Council's report on arsenic in drinking water posited the induction of aneuploidy was the most likely mechanism of arsenic carcinogenesis (National Research Council, 1999).…”

Arsenic redox transformation by Pseudomonas sp. HN-2 isolated from arsenic-contaminated soil in Hunan, China

“…Arsenic is mostly found in inorganic forms as trivalent arsenite (As(III)) or pentavalent arsenate (As(V)) (Cullen and Reimer, 1989). Among them, As(III) is generally regarded as more mobile and more toxic than As(V) (Liu et al, 2001). The affinity of As(III) for protein thiols or vicinal sulfhydryl groups makes it highly toxic.…”