Upregulation of glutathione-related genes and enzyme activities in cultured human cells by sublethal concentrations of inorganic arsenic

被引:124
作者
Schuliga, M
Chouchane, S
Snow, ET
机构
[1] Deakin Univ, Sch Biol & Chem Sci, Geelong, Vic 3125, Australia
[2] NYU, Sch Med, Nelson Inst Environm Med, Tuxedo Pk, NY 10987 USA
关键词
arsenite; glutathione; glutathione reductase; keratinocytes; gene expression;
D O I
10.1093/toxsci/70.2.183
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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 glutathione S-transferase (GST) also play key roles in these processes. In this study the regulatory effects of inorganic arsenite (As) 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 As-III 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.
引用
收藏
页码:183 / 192
页数:10
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