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Yu Du,^1,2 Nicole F. Villeneuve,¹ Xiao-Jun Wang,¹ Zheng Sun,¹ Weimin Chen,¹ Jixue Li,¹ Hongxiang Lou,² Pak Kin Wong,³ and Donna D. Zhang¹

¹Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA; ²Department of Natural Products, School of Pharmaceutical Sciences, Shandong University, Shandong, People's Republic of China; ³Aerospace and Mechanical Engineering Department, University of Arizona, Tucson, Arizona, USA

Abstract
Background: Groundwater contaminated with arsenic imposes a big challenge to human health worldwide. Using natural compounds to subvert the detrimental effects of arsenic represents an attractive strategy. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of the cellular antioxidant response and xenobiotic metabolism. Recently, activation of the Nrf2 signaling pathway has been reported to confer protection against arsenic-induced toxicity in a cell culture model.

Objectives: The goal of the present work was to identify a potent Nrf2 activator from plants as a chemopreventive compound and to demonstrate the efficacy of the compound in battling arsenic-induced toxicity.

Results: Oridonin activated the Nrf2 signaling pathway at a low subtoxic dose and was able to stabilize Nrf2 by blocking Nrf2 ubiquitination and degradation, leading to accumulation of the Nrf2 protein and activation of the Nrf2-dependent cytoprotective response. Pretreatment of UROtsa cells with 1.4 µM oridonin significantly enhanced the cellular redox capacity, reduced formation of reactive oxygen species (ROS) , and improved cell survival after arsenic challenge.

Conclusions: We identified oridonin as representing a novel class of Nrf2 activators and illustrated the mechanism by which the Nrf2 pathway is activated. Furthermore, we demonstrated the feasibility of using natural compounds targeting Nrf2 as a therapeutic approach to protect humans from various environmental insults that may occur daily.

Key words: antioxidant responsive element, antitumor, ARE, arsenic, chemoprevention, diterpenoid, Keap1, Nrf2, oridonin, oxidative stress, rubescensin. Environ Health Perspect 116:1154–1161 (2008) .  doi:10.1289/ehp.11464 available via http://dx.doi.org/ [Online 21 May 2008]

Address correspondence to D.D. Zhang, University of Arizona, College of Pharmacy, 1703 East Mabel, Tucson, AZ 85721 USA. Telephone: (520) 626-9918. Fax: (520) 626-2466. E-mail: zhang@pharmacy.arizona.edu

Y.D. and N.F.V. contributed equally to this work.

This work was supported by research grants from the National Institute of Environmental Health Sciences (1 R01 ES015010-01) and the American Cancer Society (RSG-07-154-01 -CNE) to D.D.Z. and by the China State Scholarship Fund to Y.D.

The authors declare they have no competing financial interests.

Received 8 March 2008 ; accepted 21 May 2008.