title: Critical role of cellular glutathione homeostasis for trivalent inorganic arsenite-induced oxidative damage in human bronchial epithelial cells.
abstract: Trivalent inorganic arsenic (iAs(3+)) is a powerful carcinogen that enhances the risk of lung cancer. Paradoxically, iAs(3+) also shows substantial efficacy in the treatment of lung tumors. However, the exact molecular mechanisms underlying iAs(3+)-induced toxicity and therapeutic effect in lung remain unclear. In this study, the effects of iAs(3+), sodium arsenite (NaAsO2) and arsenic trioxide (As2O3), on cell viability, apoptosis, genotoxicity and oxidative stress in cultured human bronchial epithelial cells were observed. Our results showed that NaAsO2 and As2O3 exposure could result in defects in cell proliferation and greatly enhance the level of oxidative damage. To clarify the critical role of glutathione (GSH) homeostasis in oxidative damage induced by iAs(3+), we further measured the content of GSH, ratio of GSH to GSSG, and the activities of GSH-related enzymes involved in the process of GSH synthesis, recycling and utilization. Our data demonstrated that NaAsO2 and As2O3 disrupted the balance of GSH homeostasis, and NaAsO2- and As2O3-induced oxidative damage was closely associated with the imbalance in GSH synthesis, recycling and utilization. To better understand the physiologic significance of Nrf2 in maintaining GSH-homeostasis, the expression level of Nrf2 was measured after iAs(3+) exposure. We found that the protein expression levels of Nrf2 were increased in both NaAsO2- and As2O3-treated cells. Collectively, our findings suggest that disturbed Nrf2-regulated GSH-homeostasis is associated with the oxidative damage triggered by iAs(3+), and loss of GSH homeostasis might implicate in both the pathogenesis of iAs(3+)-induced lung diseases and anticancer activity of iAs(3+).
authors.affiliation: Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oral Diseases, West China hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address: zhangzunzhen@163.com.
authors.forename: ZunZhen
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000494:pharmacology; D017670:Sodium Compounds / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D018053:Arsenites; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010087:Oxides; D017670:Sodium Compounds; C017947:sodium arsenite; D005978:Glutathione; C015001:arsenite; D001151:Arsenic; D000077237:Arsenic Trioxide
keywords: Arsenic; Glutathione homeostasis; Lung; Oxidative damage