Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver

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Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes. These gene products include proteins that catalyze reduction reactions (NAD(P)H:quinone oxidoreductase 1, Nqo1), conjugation reactions (glutathione-S-transferases, Gsts and UDP-glucuronosyltransferases, Ugts), as well as the efflux of potentially toxic xenobiotics and xenobiotic conjugates (multidrug resistance-associated proteins, Mrps). The significance of Nrf2 in the liver has been established, as livers of Nrf2-null mice are more susceptible to various oxidative/electrophilic stress-induced pathologies than wild-type mice. In contrast, both pharmacological and genetic models of hepatic Nrf2 activation are protective against oxidative/electrophilic stress. Furthermore, because certain Nrf2-target genes in the liver could affect the distribution, metabolism, and excretion of xenobiotics, the effects of Nrf2 on the kinetics of drugs and other xenobiotics should also be considered, with a special emphasis on metabolism and excretion. Therefore, this review highlights the research that has contributed to the understanding of the importance of Nrf2 in toxicodynamics and toxicokinetics, especially that which pertains to the liver.

Section snippets

Historical perspective

The first suggestion of the transcriptional regulation of cytoprotective enzymes was described with the idea of monofunctional and bifunctional inducers (Talalay, 1989). Compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatics, and β-naphthoflavone, are considered bifunctional inducers, in that they increase both phase-I [ i.e. cytochrome p450 s (Cyps), NAD(P)H quinone oxidoreductase 1 (Nqo1)] and phase-II [i.e. glutathione-S-transferases (Gsts) and

Higher susceptibility of Nrf2-null mice to hepatic injury

The potential for Nrf2 to induce many cytoprotective genes, in response to certain stimuli, permits Nrf2 to be extremely diverse in facilitating hepatoprotection from a variety of chemical-and oxidative stress-induced pathologies. Experiments have shown that targeted deletion of Nrf2, as in Nrf2-null mice, leads to enhanced susceptibility to hepatic injury. The first compound selected to illustrate the effects of a loss of Nrf2 was acetaminophen, a well-known and often used hepatotoxicant.

Distribution

Many drugs and other xenobiotics are concentrated in the liver due to their uptake by transporters. Uptake transporters expressed in the liver include the bile acid transporter Na+-taurocholate cotransporting polypeptide (Ntcp), organic anion-transporting polypeptide 1a1 (Oatp1a1), Oatp1a4, Oatp1b2, organic cation transporter 1 (Oct1), organic anion transporter 2 (Oat2), equilibrative nucleoside transporter 1 (Ent1) and Atp8b1 (Klaassen and Lu, 2008). In general, Nrf2 does not affect the mRNA

Concluding remarks

Nrf2 has emerged as a transcription factor that is capable of inducing a wide battery of genes that aid in the detoxification and elimination of xenobiotics. Evolutionarily speaking, such a transcription factor as Nrf2 is extremely advantageous in an environment where organisms are constantly bombarded with electrophilic and oxidative stress. In regard to pharmacology and toxicology, Nrf2 has evolved to be an important transcription factor. For pharmacology, Nrf2 must be considered because of

Acknowledgments

The authors would like to thank the members of the Klaassen laboratory for manuscript revision assistance. The writing of this review article was financially supported by NIH Grant DK081461.

References (99)

  • KastH.R. et al.

    Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor

    J. Biol. Chem.

    (2002)
  • LiY. et al.

    Regulation of human NAD(P)H:quinone oxidoreductase gene. Role of AP1 binding site contained within human antioxidant response element

    J. Biol. Chem.

    (1992)
  • LiuJ. et al.

    The effects of 10 triterpenoid compounds on experimental liver injury in mice

    Fundam. Appl. Toxicol.

    (1994)
  • LiuJ. et al.

    New insights into generalized hepatoprotective effects of oleanolic acid: key roles of metallothionein and Nrf2 induction

    Biochem. Pharmacol.

    (2008)
  • LuY. et al.

    Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency

    Toxicology

    (2008)
  • MarshallA.D. et al.

    Redox control of aryl sulfotransferase specificity

    Arch. Biochem. Biophys.

    (2000)
  • MaruichiT. et al.

    Transcriptional regulation of human carboxylesterase 1A1 by nuclear factor-erythroid 2 related factor 2 (Nrf2)

    Biochem. Pharmacol.

    (2010)
  • McMahonM. et al.

    Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression

    J. Biol. Chem.

    (2003)
  • MoinovaH.R. et al.

    An electrophile responsive element (EpRE) regulates beta-naphthoflavone induction of the human gamma-glutamylcysteine synthetase regulatory subunit gene. Constitutive expression is mediated by an adjacent AP-1 site

    J. Biol. Chem.

    (1998)
  • MulcahyR.T. et al.

    Identification of a putative antioxidant response element in the 5′-flanking region of the human gamma-glutamylcysteine synthetase heavy subunit gene

    Biochem. Biophys. Res. Commun.

    (1995)
  • MulcahyR.T. et al.

    Constitutive and beta-naphthoflavone-induced expression of the human gamma-glutamylcysteine synthetase heavy subunit gene is regulated by a distal antioxidant response element/TRE sequence

    J. Biol. Chem.

    (1997)
  • OkadaK. et al.

    Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems

    Biochem. Biophys. Res. Commun.

    (2009)
  • OkawaH. et al.

    Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity

    Biochem. Biophys. Res. Commun.

    (2006)
  • ReddyB.S. et al.

    Effect of dietary butylated hydroxyanisole on methylazoxymethanol acetate-induced toxicity in mice

    Food. Chem. Toxicol.

    (1982)
  • ReismanS.A. et al.

    Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes

    Biochem. Pharmacol.

    (2009)
  • ReismanS.A. et al.

    CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes

    Toxicol. Appl. Pharmacol.

    (2009)
  • RushmoreT.H. et al.

    The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity

    J. Biol. Chem.

    (1991)
  • SeeligG.F. et al.

    Reversible dissociation of gamma-glutamylcysteine synthetase into two subunits

    J. Biol. Chem.

    (1984)
  • ShinS. et al.

    Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide

    Eur. J. Pharmacol.

    (2009)
  • TalalayP.

    Mechanisms of induction of enzymes that protect against chemical carcinogenesis

    Adv. Enzyme. Regul.

    (1989)
  • ToyamaT. et al.

    Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity

    Biochem. Biophys. Res. Commun.

    (2007)
  • VoN. et al.

    CREB-binding protein and p300 in transcriptional regulation

    J. Biol. Chem.

    (2001)
  • XuW. et al.

    The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis

    Lab. Invest.

    (2008)
  • ZhuM. et al.

    Functional characterization of transcription regulators that interact with the electrophile response element

    Biochem. Biophys. Res. Commun.

    (2001)
  • AlnoutiY. et al.

    Regulation of sulfotransferase enzymes by prototypical microsomal enzyme inducers in mice

    J. Pharmacol. Exp. Ther.

    (2008)
  • BeyerT.A. et al.

    Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance

    EMBO. J.

    (2008)
  • BobergE.W. et al.

    Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1′-sulfooxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1′-hydroxysafrole in mouse liver

    Cancer Res.

    (1983)
  • BuckleyD.B. et al.

    Induction of mouse UDP-glucuronosyltransferase mRNA expression in liver and intestine by activators of aryl-hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and nuclear factor erythroid 2-related factor 2

    Drug. Metab. Dispos.

    (2009)
  • ChanK. et al.

    NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development

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

    (1996)
  • ChanK. et al.

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

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

    (2001)
  • ChengX. et al.

    Tissue distribution and ontogeny of mouse organic anion transporting polypeptides (Oatps)

    Drug. Metab. Dispos.

    (2005)
  • ChengX. et al.

    Regulation of mouse organic anion-transporting polypeptides (Oatps) in liver by prototypical microsomal enzyme inducers that activate distinct transcription factor pathways

    Drug. Metab. Dispos.

    (2005)
  • CrocenziF.A. et al.

    Galactosamine prevents ethinylestradiol-induced cholestasis

    Drug. Metab. Dispos.

    (2006)
  • DekantW. et al.

    Glutathione-dependent bioactivation of xenobiotics

    Xenobiotica

    (1993)
  • DuY. et al.

    Oleanolic acid protects against myocardial ischemia-reperfusion injury by enhancing mitochondrial antioxidant mechanism mediated by glutathione and alpha-tocopherol in rats

    Planta. Med.

    (2006)
  • EnomotoA. 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)
  • EvansW.E. et al.

    Pharmacogenomics: translating functional genomics into rational therapeutics

    Science

    (1999)
  • GaoD. et al.

    Antidiabetic and antioxidant effects of oleanolic acid from Ligustrum lucidum Ait in alloxan-induced diabetic rats

    Phytother. Res.

    (2009)
  • HayesJ.D. et al.

    The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin

    Biochem. Soc. Trans.

    (2000)
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