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.

The mechanistic basis of arsenicosis: Pathogenesis of skin cancer

“…Our findings implicated hydroxyl and hydrogen peroxide ROS in arsenic-induced genotoxicity using Chinese hamster ovary chromosomes and in epidermal keratinocytes. This confirmed the importance of ROS and the reduction of intracellular thiols, particularly glutathione, in the toxicity of arsenic [35]. In a subsequent investigation, we employed two complementary approaches to determine the cellular organelle responsible for ROS production in arsenic cytotoxicity.…”

“…An overwhelming body of evidence has described arsenic’s ability to cause oxidative and nitrosative stress through the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [1,29,34,35]. Arsenic-induced oxidative stress has been measured directly by assaying ROS production and indirectly through the evaluation of reactive byproducts such as 8-hydroxydeoxyguanosine and lipid peroxides.…”

Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation

“…This inhibition in activity of the antioxidant enzymes may lead to disturbed anti-oxidant/ pro-oxidant ratio resulting in oxidative stress induced damage. Additionally, the major event that follows the abundant accumulation of H 2 O 2 and super-oxide anion is the oxidative deterioration of polyunsaturated fatty acids [32]. Therefore, we further measured MDA production, an indicator of lipid-peroxidation, following NaAsO 2 and menadione treatment alone or in combination.…”

(-)-Epigallocatechin-3-Gallate Inhibits Arsenic-Induced Inflammation and Apoptosis through Suppression of Oxidative Stress in Mice

“…These factors deteriorate in arsenic-related dysfunction of the immune system, particular immunosuppression [7]. Additionally, such alterations of these factors in intracellular and intercellular homeostasis probably lead to cell death and mitochondrial dysfunction, thereby strengthening the activation of stress-related genes [3, 8]. Meanwhile, arsenic exposure through contaminated food materials is quite common in areas with high levels of arsenic in the groundwater, which is becoming an urgent issue in the field of public health.…”