Review
Nrf2 signaling: An adaptive response pathway for protection against environmental toxic insults

https://doi.org/10.1016/j.mrrev.2007.11.006Get rights and content

Abstract

Human exposures to environmental toxicants have been associated with development of a number of diseases. Animal experiments have identified a number of cytoprotective enzymes under the transcriptional control of NF-E2-related factor 2 (Nrf2) including electrophile conjugation and antioxidative enzymes and enzymes responsible for the production of antioxidants, reducing equivalents and cofactors. The up-regulation of these enzymes represents an adaptive response which occurs in the face of exposure to electrophilic or oxidative compounds thereby leading to enhanced metabolism of these molecules or their reactive metabolites. This adaptive response is regulated by an interaction between Keap1 and Nrf2 in which the exposure to reactive molecules is sensed either directly by Keap1 or indirectly by cellular signaling cascades resulting in activation of Nrf2 transcriptional regulation. The Nrf2-mediated adaptive response has been shown to attenuate toxicity and carcinogenesis during electrophile or oxidative stress as well as inflammation in rodent models. The cytoprotective attributes of the Nrf2 signaling pathway have been targeted for chemoprevention as administration of Nrf2-inducing agents has been shown to result in decreased carcinogenesis in animal models and altered carcinogen metabolism in humans. On the other hand, polymorphisms in the Nrf2 signaling pathway can lead to differential susceptibility to disease while mutations in the Nrf2 signaling pathway have been shown to an effective mechanism for cancer cells to evade chemotherapy. Overall, the Nrf2 cytoprotective adaptive response has evolved to be a powerful protective strategy for organisms against exposure to environmental toxicants and may provide insight into differential disease susceptibilities across populations and responses to therapies designed to alleviate these conditions.

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.

References (62)

  • M. Kwak et al.

    Chemoprevention by 1,2-dithiole-3-thiones through induction of NQO1 and other phase 2 enzymes

    Methods Enzymol.

    (2004)
  • W. Osburn et al.

    Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion

    Arch. Biochem. Biophys.

    (2006)
  • N. Burton et al.

    In vivo modulation of the Parkinsonian phenotype by Nrf2

    Neurotoxicology

    (2006)
  • M. Valko et al.

    Free radicals, metals and antioxidants in oxidative stress-induced cancer

    Chem. Biol. Interact.

    (2006)
  • Y. Aoki et al.

    Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust

    Toxicol. Appl. Pharmacol.

    (2001)
  • J. Hayes et al.

    The double-edged sword of Nrf2: subversion of redox homeostasis during the evolution of cancer

    Mol. Cell.

    (2006)
  • M. Kobayashi et al.

    Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation

    Antioxid. Redox. Signal

    (2005)
  • K. Tong et al.

    Keap1 recruits Neh2 through binding to ETGE and DLG motifs:characterization of the two-site molecular recognition model

    Mol. Cell Biol.

    (2006)
  • S. Cullinan et al.

    The keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase

    Mol. Cell. Biol.

    (2004)
  • A.T. Dinkova-Kostova et al.

    The role of keap1 in cellular protective responses

    Chem. Res. Toxicol.

    (2005)
  • N. Wakabayashi et al.

    Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • H. Motohashi et al.

    Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • M. Leonard et al.

    Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury

    FASEB J.

    (2006)
  • R.K. Thimmulappa et al.

    Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray

    Cancer Res.

    (2002)
  • K. Chan et al.

    An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • A. Enomoto et al.

    High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes

    Toxicol. Sci.

    (2001)
  • C. Goldring et al.

    Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice

    Hepatology

    (2004)
  • M. Ramos-Gomez et al.

    Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • M. Ramos-Gomez et al.

    Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice

    Carcinogenesis

    (2003)
  • K. Iida et al.

    Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis

    Cancer Res.

    (2004)
  • P. Gong et al.

    Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1

    Hepatology

    (2006)
  • Cited by (467)

    View all citing articles on Scopus
    View full text