Oxidative stress and cytotoxic effects of silver ion in mouse lung macrophages J774.1 cells.
Silver is commonly used as a disinfectant, and chronic exposure to silver may cause argyria, resulting in a gray-blue discoloration of human skin. However, the mechanism for cellular toxicity of silver has not been well explained. We studied the mode of cell death, the ratio of glutathione disulfide/glutathione, induction of metallothionein and activation of mitogen-activated protein kinases in J774.1 cells together with activation of antioxidant responsive element and nuclear factor-κB in CHO cells following exposure to silver ion (Ag+) to investigate the mechanism by which Ag+causes lethal effects. Ag+increased phosphorylation levels of extracellular signal-regulated, c-Jun N-terminal and p38 mitogen-activated protein kinases and remarkably increased the ratio of glutathione disulfide/glutathione in both a time- and concentration-dependent manner. Luciferase reporter gene assays revealed that antioxidant responsive element and nuclear factor-κB were activated following exposure to Ag+. In addition, exposure to Ag+increased the mRNA and protein levels of metallothionein. We investigated whether or not Ag+killed J774.1 cells by inducing apoptosis. Ag+increased the activity of caspase-3/7 which was abrogated by caspase 3 and pan-caspase inhibitors. However, these inhibitors did not ameliorate the cytotoxic effects of Ag+, suggesting that Ag+causes oxidative stress, which leads to necrotic rather than apoptotic cell death in J774.1 cells by decreasing functional sulfhydryl groups including glutathione in the cells. Copyright © 2016 John Wiley & Sons, Ltd.
Department of Environmental Health Research, National Institute of Environmental Research, Republic of Korea.
Ilseob
I
Shim
Department of Environmental Health Research, National Institute of Environmental Research, Republic of Korea.
Kyunghee
K
Choi
Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Japan.
Seishiro
S
Hirano
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D017930:Genes, Reporter / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects*; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects*; D012834:Silver / Q000737:chemistry / Q000633:toxicity*
D061945:Caspase Inhibitors; D012834:Silver; D008668:Metallothionein; D020169:Caspases; D005978:Glutathione
Caspase; Glutathione; MAP Kinase; Macrophage; Metallothionein; Silver ion