ReviewNrf2 signaling: An adaptive response pathway for protection against environmental toxic insults
Section snippets
The Nrf2 signaling pathway
Nrf2 is a member of the Cap-N-Collar transcription factor family and recognizes the antioxidant response element (ARE) in the promoter of target genes [2]. Normally, under basal conditions Nrf2 is bound to Keap1 in the cytoplasm due to an interaction between a single Nrf2 protein and a Keap1 dimer [3]. Keap1 serves as a substrate linker protein for interaction of the Cul3-based E3-ubiquitin ligase complex with Nrf2 leading to ubiquitination of Nrf2 and proteosomal degradation [4].
Exposure to a
Nrf2-dependent attenuation of electrophile toxicity
The importance of Nrf2 in protection against reactive electrophiles was first demonstrated using acetaminophen. N0 mice displayed greater hepatotoxicity, manifested in increased serum ALT values and altered hepatic histology, following acetaminophen exposure, relative to WT mice [17], [18]. The hepatoprotective effect of Nrf2 was shown to be due to both increased expression of UDP-glucuronosyltransferase 1A6 presumably leading to increased glucuronidation and excretion of acetaminophen, and the
Importance of Nrf2 signaling in protection against oxidative toxicity
Increased oxidative stress has been implicated in the etiology of a number of acute and chronic diseases linked to exposures to environmental toxicants. Reactive species can react with lipids, protein and DNA. In vitro studies have illustrated the importance of the Nrf2-regulated signaling pathway in protection against oxidative stress-mediated cytotoxicity following exposure to oxidants. For example, mouse embryonic fibroblasts (MEF) from N0 mice had increased sensitivity to superoxide anion
Anti-inflammatory role of Nrf2 signaling
Numerous in vivo studies have illustrated that Nrf2 plays an important role in modulating inflammation in a variety of experimental models. N0 mice have been shown to exhibit increased susceptibility to tobacco smoke- [36] and elastase- [37] mediated emphysema, allergen-driven airway inflammation [38], carrageenan-induced pleurisy [39] and dextran sulfate sodium (DSS)-mediated colitis [40], compared to WT mice. For example, enlarged alveoli and increased lung compliance was detected in the
Targeting the Nrf2 signaling pathway for chemoprevention
The activation of the Nrf2 signaling by administration of Nrf2-inducing small molecules has been shown to be chemoprotective in a number of animal models of carcinogenesis and the potential for this strategy in humans is beginning to be demonstrated. The cancer chemopreventive activity of oltipraz, a drug originally developed for the treatment of schistosomiasis, was first demonstrated by Wattenburg and Bueding. Oltipraz administration resulted in decreased tumor formation in a mouse model of B[
Nrf2 signaling pathway polymorphisms
Recently, Marzec et al. [53] identified a number of single nucleotide polymorphisms (SNP) in the promoter region of Nrf2 present in human subjects across multiple ethnic groups. Functional analysis of these polymorphisms showed that one of the SNPs resulted in decreased in vitro binding of Nrf2 to an ARE promoter following exposure to Nrf2-inducing stresses [53]. Importantly, individuals with this SNP were found to be more likely to develop acute lung injury, relative to individuals with a
Conclusions
Up-regulation of Nrf2 cytoprotective enzymes possesses great potential to effectively attenuate toxicity following exposure to environmental toxicants. The protein products of Nrf2-regulated cytoprotective genes can target multiple steps along the pathway of toxicity following exposure to electrophilic and oxidative xenobiotics, as illustrated in Fig. 2. This adaptive response is energetically favorable in that enhanced transcription of cytoprotective genes only occurs through the cellular
Acknowledgements
Our work on cancer chemoprevention is supported by NIH grants RO1CA39416, RO1CA94076, PO1ES06052 and P50CA88843. William O. Osburn is supported by NIEHS training grant ES07141.
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