The Role of Glutathione in Copper Metabolism and Toxicity

Freedman, Jonathan H.; Ciriolo, Maria Rosa; Peisach, Jack

doi:10.1016/s0021-9258(18)83589-x

Cited by 516 publications

(103 citation statements)

References 44 publications

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“…GSH was previously reported as the first line of defense against heavy metals‐induced toxicity. [ 67,68 ] A significant depletion in the GSH content in Cr(VI)‐exposed hsp70 ‐KO and ‐KD larvae was evidenced concurrent with its reversal in similarly exposed hsp70‐ overexpression larvae. This was further evidenced by a significant positive correlation drawn between hsp70 and the GSH content.…”

Section: Discussionmentioning

confidence: 96%

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

Chaouhan

Jha

Patel

et al. 2021

J Biochem & Molecular Tox

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Hexavalent chromium [Cr(VI)] is a genotoxic chemical, and in the chemical‐exposed organism, oxidative stress is one of the leading causative mechanisms of genotoxicity. Heat shock protein‐70 (Hsp70) is reported to be modulated in environmental chemical exposed organisms. Inadequate information on the protective role of Hsp70 in chemical‐induced DNA lesions prompted us to investigate this possibility in a well‐studied genetically tractable in vivo model Drosophila melanogaster. In the midgut cells of Cr(VI)‐exposed hsp70‐knockout (KO), ‐knockdown (KD), and ‐overexpression Drosophila strains, no significant change in double‐strand breaks generation was observed in comparison to similarly exposed w 1118 and the respective genetic control strain after 48 h. Therefore, the role of hsp70 was investigated on oxidative DNA damage induction in the exposed organisms after 24 h. Oxidized DNA lesions (particularly oxidized purine‐based lesions), 8‐oxo‐dG level, and oxidative stress endpoints were found to be significantly elevated in hsp70‐KO and ‐KD strains in comparison to similarly exposed w 1118 and respective genetic control strain. On the contrary, in ubiquitous hsp70‐overexpression strain exposed to Cr(VI), these endpoints were significantly lowered concurrently with increased GSH level through elevated gclc, and gclm expression, Gclc level, and GCL activity. The study suggests that as a consequence of hsp70 overexpression, the augmented GSH level in cells vis‐a‐vis GSH de novo synthesis can counteract Cr(VI)‐induced oxidized DNA lesions.

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Section: Discussionmentioning

confidence: 96%

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

Chaouhan

Jha

Patel

et al. 2021

J Biochem & Molecular Tox

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“…Another study reported a dose-dependent increase in DNA fragmentation observed in primary cultures of rat and human kidney cells exposed to chemicals carcinogenic to rat kidney (Robbiano et al, 2004). Although varying degrees of vulnerability to oxidative damage and ROS formation have been reported in cell lines (Oliveira et al, 2008), the cause is not readily evident, as certain mammalian cell lines are reported to possess a greater degree of metal sensitivity (Freedland et al, 1989). Another reason could be differences in the DNA repair capabilities between cell lines, as Kienzler et al (2013) reported that RTgill-W1 and RTL-W1 cells possess functioning nucleotide excision repair and photoactivation repair on exposure to UV light.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the genotoxic potential of water impacted by acid mine drainage from a coal mine in Mpumalanga, South Africa, using the Ames test and Comet assay

Iji

Njoya

Madikizela

et al. 2021

WSA

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Several potential genotoxins found in water samples arise from anthropogenic activities. Acid mine effluent resulting from coal mining poses serious environment concerns all over the world. The use of toxicity tests to evaluate the quality of streams add value by providing site-specific toxicological data. Treatment systems such as the use of natural wetlands (passive) or conventional physical and chemical pH-neutralised processes (active) are employed mainly to meet certain water quality guidelines. Nonetheless, potential genotoxins or residues remain which influence the quality of discharged effluents. The objective of this study was to evaluate the genotoxic potential of acid mine drainage (AMD) released into a natural stream following treatment by passive and active methods. This study aimed to identify the extent of AMD mutagenicity and genotoxicity to African Vero monkey kidney cell line and a fish gill cell line (RTgill-W1) using two assays, the Ames test, and the comet assay, as a rapid and effective screening tool. The Ames test performed without metabolic activation using Salmonella typhimurium TA98 and TA100 strains showed no indication of mutagenicity in the water samples tested. Differing results were however obtained for the comet assay using the African Vero monkey kidney cell line and a fish gill cell line (Rtgill-W1), which revealed DNA fragmentation and variations in morphologies indicative of genotoxicity in the water samples following the two treatment processes. A significant reduction in DNA damage was observed in water samples following active treatment of the AMD, evidenced by reduced damage frequency and a lowered comet score. This bioassay confirms the urgency of integrating high-throughput screening in aquatic toxicity assessment at genetic levels, giving further evidence that in-vitro bioassays can be incorporated for use in short-term genotoxicity assays. The result suggests that the comet assay proved sensitive at detecting genotoxicity, supporting the integration of this into environmental monitoring frameworks targeted at AMD-contaminated sites.

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“…One major copper recipient from Ctr1 is the reduced form of glutathione (GSH), which is present within the cell at low millimolar concentrations in order to maintain the redox status of the cytosol while also functioning as an intracellular copper sink. A number of independent groups have shown that GSH can supply copper to chaperones such as Ccs [22,92,105]. GSH likely serves as a general copper reservoir for cytosolic copper-binding proteins.…”

Section: Glutathionementioning

confidence: 99%

“…In mammals, it has been demonstrated that Sod1 can be activated in a Ccs-independent manner and that GSH plays an essential, if not well defined, role in this pathway [22]. For lower eukaryotes (e.g., yeast), GSH cannot unilaterally activate Sod1, but GSH has shown the ability to provide copper for activation in the presence of Ccs [34,41].…”

Section: Glutathionementioning

confidence: 99%

“…MT genes are upregulated, similar to those coding for Sod1, during times of oxidative stress [40]. GSH is an abundant antioxidant tripeptide present within the cytosol that, amongst other functions, can bind Cu(I) and has even been shown to deliver this cargo to Sod1 [22,41] (Figure 1). This review will focus on the known and proposed copper transport pathways for Sod1.…”

Section: Introductionmentioning

confidence: 99%

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Copper Sources for Sod1 Activation

et al. 2020

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Copper ions (i.e., copper) are a critical part of several cellular processes, but tight regulation of copper levels and trafficking are required to keep the cell protected from this highly reactive transition metal. Cu, Zn superoxide dismutase (Sod1) protects the cell from the accumulation of radical oxygen species by way of the redox cycling activity of copper in its catalytic center. Multiple posttranslational modification events, including copper incorporation, are reliant on the copper chaperone for Sod1 (Ccs). The high-affinity copper uptake protein (Ctr1) is the main entry point of copper into eukaryotic cells and can directly supply copper to Ccs along with other known intracellular chaperones and trafficking molecules. This review explores the routes of copper delivery that are utilized to activate Sod1 and the usefulness and necessity of each.

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The Role of Glutathione in Copper Metabolism and Toxicity

Cited by 516 publications

References 44 publications

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

Cr(VI)‐induced DNA damage is lessened by the modulation of hsp70 via increased GSH de novo synthesis in Drosophila melanogaster

Evaluation of the genotoxic potential of water impacted by acid mine drainage from a coal mine in Mpumalanga, South Africa, using the Ames test and Comet assay

Copper Sources for Sod1 Activation

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