Glutathione protects cells against arsenite-induced toxicity

Habib, Geetha M.; Shi, Zhenfeng; Lieberman, Michael W.

doi:10.1016/j.freeradbiomed.2006.10.036

Cited by 53 publications

(30 citation statements)

References 43 publications

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“…Using GSH-deficient GCS-2 cells, we have previously demonstrated that arsenite induces ubiquitination and apoptotic cell death [cytochrome C leakage and DNA fragmentation; Habib et al, 2007] and that p53 regulates Hsp90β during arsenite-induced cytotoxicity [Habib et al, 2009]. In the current study, we show that arsenite down-regulates Akt and c-Fos by ubiquitination, decreases AP-1 activity and causes cell cycle dysregulation and apoptotic cell death.…”

Section: Introductionsupporting

confidence: 57%

Arsenite causes down‐regulation of Akt and c‐Fos, cell cycle dysfunction and apoptosis in glutathione‐deficient cells

Habib

2010

J of Cellular Biochemistry

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Arsenic is a well known environmental toxicant but the mechanism by which it causes cytotoxicity is poorly understood. Arsenite induces apoptosis in glutathione (GSH)-deficient GCS-2 cells by causing cell cycle dysfunction and down-regulating critical signaling pathways. This study was designed to examine the effect of arsenite on redox-sensitive phosphatidylinositol 3-kinase (PI3K)/Akt, a signaling pathway involved in cell survival and growth, and transcription factor, activating protein-1 (AP-1). Arsenite significantly diminished Akt and c-Fos levels and caused accelerated degradation of these proteins by ubiquitnation. Arsenite also induced cell cycle arrest and apoptosis. The cell cycle arrest involved the down-regulation of cyclin A2, cyclin D1, cyclin E, cyclin dependent kinases (CDK) 2, CDK4, and CDK6. Apoptosis involved downregulation of anti-apoptotic proteins Bcl-2, Bcl-xL, survivin, and inhibitor of apoptosis protein (IAP) and up-regulation of pro-apoptotic protein Bax. Taken together, our results suggest that a possible mechanism of arsenite-induced toxicity under low/no GSH conditions, is to negatively regulate GCS-2 cell proliferation by attenuating Akt and AP-1 by ubiquitination and causing cell cycle dysfunction and apoptosis.

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Section: Introductionsupporting

confidence: 57%

Arsenite causes down‐regulation of Akt and c‐Fos, cell cycle dysfunction and apoptosis in glutathione‐deficient cells

Habib

2010

J of Cellular Biochemistry

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“…In cell lines with intrinsic low glutathione content, arsenic markedly induced lipid peroxidation assessed as malondialdehyde levels compared to cells with normal glutathione content; this lipid damage was prevented by pretreatment with glutathione or its precursor [Habib et al, 2007]. In another study, reduced levels of glutathi- Environmental and Molecular Mutagenesis.…”

Section: Discussionmentioning

confidence: 94%

“…Conse-quently, exposure to arsenic compounds leads to increased levels of oxidative lesions in DNA, especially 8-hydroxy-2 0 -deoxyguanosine, products of lipid peroxidation, and protein carbonyls [Wanibuchi et al, 1997;Matsui et al, 1999;Yamanaka et al, 2001;Bau et al, 2002;Eblin et al, 2006;Wang et al, 2007]. An important feature of arsenic-induced toxic effects is related to its high ability of reacting with protein and nonprotein thiol groups resulting in an alteration of critical cellular pathways [Valko et al, 2006;Habib et al, 2007]. Additionally, it has been shown that reduced glutathione content is inversely correlated with sensitivity of cells to arsenic exposure [Nakagawa et al, 2002;Habib et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

“…An important feature of arsenic-induced toxic effects is related to its high ability of reacting with protein and nonprotein thiol groups resulting in an alteration of critical cellular pathways [Valko et al, 2006;Habib et al, 2007]. Additionally, it has been shown that reduced glutathione content is inversely correlated with sensitivity of cells to arsenic exposure [Nakagawa et al, 2002;Habib et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress and antioxidant defenses in goldfish liver in response to short‐term exposure to arsenite

Bagnyukova

Luzhna

Pogribny

et al. 2007

Environ and Mol Mutagen

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Arsenic is an environmental pollutant capable of causing oxidative stress, disturbance of metabolism, and cancer development. The present study was undertaken to investigate the effects of exposure to sodium arsenite on the glutathione pool, lipid peroxidation, protein carbonyl levels, global DNA methylation, and activities of six antioxidant enzymes in goldfish liver. In a preliminary experiment, 7-day exposure to 200 microM sodium arsenite, but not 10 or 100 microM, disturbed the glutathione status. A detailed investigation of oxidative stress development and antioxidant responses was further examined during different periods of exposure to 200 microM sodium arsenite. This treatment increased lipid peroxide levels after 1 and 4 days of exposure but did not affect thiobarbituric acid reactive substances and protein carbonyls. Oxidized glutathione and the oxidative stress index rose after 4 days, but de novo glutathione synthesis decreased both parameters after 7 days. Activities of the main antioxidant enzymes-superoxide dismutase, catalase, and glutathione peroxidase, were elevated after longer periods of exposure, indicating an enhanced antioxidant response. Arsenite exposure led to DNA hypomethylation, which is an early marker of disturbed epigenetic regulations. The findings suggest that goldfish livers cope with arsenic-induced oxidative stress mainly through adaptive changes in the glutathione pool and antioxidant enzymes.

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“…4a demonstrates that GSH levels in the 10 −3 , 10 −2 , 10 −1 and 1 mg/l PtNP-treated L6 cells increased significantly without concentration dependency compared with that of the untreated control cells ( ** p<0.01). Such elevated GSH levels are expected to act on ROS directly, thereby protecting the cells from oxidative stress [44,45]. The level of intracellular GSH induced by 10 mg/l was similar to that of the control cells.…”

Section: Cellular Gsh and Gssg Content Affected By Ptnpsmentioning

confidence: 66%

Low Concentration Platinum Nanoparticles Effectively Scavenge Reactive Oxygen Species in Rat Skeletal L6 Cells

Nakanishi¹,

Hamasaki²,

Kinjo³

et al. 2013

Nano BioMed ENG

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Prolonged exposure to excessive reactive oxygen species (ROS) increases risk factors for many diseases. Therefore, elimination of ROS as well as prevention of its production becomes critically important. In the present study, we evaluated the levels of cytotoxicity and ROS scavenging activity induced by synthetic platinum nanoparticles (PtNPs). Average size of synthesized PtNPs was 2.2 nm. Synthetic PtNPs were found to scavenge both induced and endogenous H 2 O 2 significantly in L6 rat skeletal muscle cells at a very low concentration (10 −2 mg/l). To investigate the mechanism of action, the hierarchical oxidative stress model was used as an experimental model. To evaluate this possibility, we assessed glutathione concentration and gene levels of several antioxidant enzymes in PtNPs-treated (10 −3 -10 mg/l) L6 cells. Reduced glutathione (GSH) was increased in the range of 10 −3 -1 mg/l, but not in the 10 mg/l PtNP-treated cells. The GSH/GSSG ratio increased significantly at 1 mg/l and decreased in the 10 mg/l PtNPtreated cells. Most of the gene transcripts for oxidative stress inducible heme oxygenase-1 (HO-1), glutathione reductase (GR), copper-zinc superoxide dismutase (CuZn-SOD), manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and catalase were increased significantly by PtNPs at 10 −1 -10 mg/l. Such upregulatory effects induced by synthetic PtNPs at high concentrations (1-10 mg/l) in L6 cells can be explained by the hierarchical oxidative stress model. However, the cellular responses induced by low levels (10 −3 -10 −2 mg/l) of PtNPs could not be fully explained by this model.

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Glutathione protects cells against arsenite-induced toxicity

Cited by 53 publications

References 43 publications

Arsenite causes down‐regulation of Akt and c‐Fos, cell cycle dysfunction and apoptosis in glutathione‐deficient cells

Arsenite causes down‐regulation of Akt and c‐Fos, cell cycle dysfunction and apoptosis in glutathione‐deficient cells

Oxidative stress and antioxidant defenses in goldfish liver in response to short‐term exposure to arsenite

Low Concentration Platinum Nanoparticles Effectively Scavenge Reactive Oxygen Species in Rat Skeletal L6 Cells

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