In Vivo Effect of Arsenic Trioxide on Keap1-p62-Nrf2 Signaling Pathway in Mouse Liver: Expression of Antioxidant Responsive Element-Driven Genes Related to Glutathione Metabolism
Arsenic is a Group I human carcinogen, and chronic arsenic exposure through drinking water is a major threat to human population. Liver is one of the major organs for the detoxification of arsenic. The present study was carried out in mice in vivo after arsenic treatment through drinking water at different doses and time of exposure. Arsenic toxicity is found to be mediated by reactive oxygen species. Nuclear factor (erythroid-2 related) factor 2 (Nrf2)/Keap1 (Kelch-like ECH-associated protein 1)/ARE (antioxidant response element)—driven target gene system protects cells against oxidative stress and maintains cellular oxidative homeostasis. Our result showed 0.4？ppm, 2？ppm, and 4？ppm arsenic trioxide treatment through drinking water for 30 days and 90 days induced damages in the liver of Swiss albino mice as evidenced by histopathology, disturbances in liver function, induction of heat shock protein 70, modulation of trace elements, alteration in reduced glutathione level, glutathione-s-transferase and catalase activity, malondialdehyde production, and induction of apoptosis. Cellular Nrf2 protein level and mRNA level increased in all treatment groups. Keap1 protein as well as mRNA level decreased concomitantly in arsenic treated mice. Our study clearly indicates the important role of Nrf2 in activating ARE driven genes related to GSH metabolic pathway and also the adaptive response mechanisms in arsenic induced hepatotoxicity. 1. Introduction Arsenic (As), a Group I human carcinogen, is the major source of ground water contamination all over the world. The permissible limit of As, set by World Health Organization (WHO) is 10 parts per billion (ppb). However, in many countries including India and Bangladesh, people are consuming As through drinking water at much higher level. Up to 50？ppm of As is reported in many states in the USA [1]. Fu et al. [2] estimated that 13 million Americans were exposed to more than 0.01？ppm of arsenic through public water systems by 2006. According to the report of the Prevention and Treatment Academy of China, this number reached 14.66 million in China [3] where in many places individuals were exposed up to a level of 1？ppm of As [4]. In West Bengal, India As concentrations in some tube wells is as high as 3.4？ppm [5]. Chronic arsenic exposure has become a great concern than acute exposure mainly because of its carcinogenic effects [6, 7]. Environmental exposure to arsenic is generally in the form of either arsenite (As3+) or arsenate (As5+) which undergoes redox conversion, where arsenite is the predominant form in
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