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- Title
Upregulation of Glutathione-Related Genes and Enzyme Activities in Cultured Human Cells by Sublethal Concentrations of Inorganic Arsenic.
- Authors
Schuliga, Michael; Chouchane, Salem; Snow, Elizabeth T.
- Abstract
Inorganic arsenic (iAs), a known human carcinogen, acts as a tumor promoter in part by inducing a rapid burst of reactive oxygen species (ROS) in mammalian cells. This causes oxidative stress and a subsequent increase in the level of cellular glutathione (GSH). Glutathione, a ubiquitous reducing sulfhydryl tripeptide, is involved in ROS detoxification and its increase may be part of an adaptive response to the oxidative stress. Glutathione related enzymes including glutathione reductase (GR) and glutathioneS-transferase (GST) also play key roles in these processes. In this study the regulatory effects of inorganic arsenite (AsIII) on the activities of GSH-related enzymes were investigated in cultured human keratinocytes. Substantial increases in GR enzyme activity and mRNA levels were shown in keratinocytes and other human cell lines after exposure to low, subtoxic, micromolar concentrations of AsIII for 24 h. Upregulation of GSH synthesis paralleled the upregulation of GR as shown by increases in glutamate-cysteine lyase (GCL) enzyme activity and mRNA levels, cystine uptake, and intracellular GSH levels. Glutathione S-transferase activity was also shown to increase slightly in keratinocytes, but not in fibroblasts or breast tumor cells. Overall the results show that sublethal arsenic induces a multicomponent response in human keratinocytes that involves upregulation of parts, but not all of the GSH system and counteracts the acute toxic effects of iAs. The upregulation of GR has not previously been shown to be an integral part of this response, although GR is critical for maintaining levels of reduced GSH.
- Subjects
PHYSIOLOGICAL effects of arsenic; PHYSIOLOGICAL effects of glutathione; GLUTATHIONE transferase; KERATINOCYTES; CELL lines
- Publication
Toxicological Sciences, 2002, Vol 70, Issue 2, p183
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/70.2.183