Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity

• Published in: Toxicology and applied pharmacology 2007-12, Vol.225 (2), p.206-213
• Main Authors: Wang, Xiao-Jun, Sun, Zheng, Chen, Weimin, Eblin, Kylee E., Gandolfi, Jay A., Zhang, Donna D.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Anticarcinogenic Agents - pharmacology; ANTIOXIDANTS; Antioxidants - metabolism; ARSENIC; Arsenicals - adverse effects; Arsenite; Arsenites - toxicity; Biological and medical sciences; BLADDER; Carcinogenesis, carcinogens and anticarcinogens; Cell Line; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; Embryo, Mammalian - cytology; Embryo, Mammalian - drug effects; EMBRYOS; Environmental Pollutants - toxicity; Enzyme Inhibitors - pharmacology; FIBROBLASTS; Fibroblasts - cytology; Fibroblasts - drug effects; Gene Expression Regulation; Humans; Hydroquinones - pharmacology; Isothiocyanates; Keap1; Medical sciences; Metals and various inorganic compounds; MICE; MMA(III); NF-E2-Related Factor 2 - metabolism; Nrf2; PUBLIC HEALTH; RNA, Small Interfering - metabolism; Sodium Compounds - toxicity; Thiocyanates - pharmacology; TOXICITY; Toxicology; TRANSCRIPTION FACTORS; Tumors; Urinary Bladder - cytology; Urothelium - drug effects; Urothelium - metabolism; UROtsa
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2007.07.016

Arsenic is widely spread in our living environment and imposes a big challenge on human health worldwide. Arsenic damages biological systems through multiple mechanisms including the generation of reactive oxygen species. The transcription factor Nrf2 regulates the cellular antioxidant response that protects cells from various insults. In this study, the protective role of Nrf2 in arsenic toxicity was investigated in a human bladder urothelial cell line, UROtsa. Using a UROtsa cell line stably infected with Nrf2-siRNA, we clearly demonstrate that compromised Nrf2 expression sensitized the cells to As(III)- and MMA(III)-induced toxicity. On the other hand, the activation of the Nrf2 pathway by tert-butylhydroquinone (tBHQ) and sulforaphane (SF), the known Nrf2-inducers, rendered UROtsa cells more resistant to As(III) and MMA(III). Furthermore, the wild-type mouse embryo fibroblast (WT-MEF) cells were protected from As(III)- and MMA(III)-induced toxicity following Nrf2 activation by tBHQ or SF, whereas neither tBHQ nor SF conferred protection in the Nrf2 −/−MEF cells, demonstrating that tBHQ- or SF-mediated protection against As(III)- and MMA(III)-induced toxicity depends on Nrf2 activation. These results, obtained by both loss of function and gain of function analyses, clearly demonstrate the protective role of Nrf2 in arsenic-induced toxicity. The current work lays the groundwork for using Nrf2 activators for therapeutic and dietary interventions against adverse effects of arsenic.