Nrf2 in liver toxicology

  • Keiko TaguchiEmail author
  • Thomas W. Kensler


Liver plays essential roles in the metabolism of many endogenous chemicals and exogenous toxicants. Mechanistic studies in liver have been at the forefront of efforts to probe the roles of bioactivation and detoxication of environmental toxins and toxicants in hepatotoxicity. Moreover, idiosyncratic hepatoxicity remains a key barrier in the clinical development of drugs. The now vast Nrf2 field emerged in part from biochemical and molecular studies on chemical inducers of hepatic detoxication enzymes and subsequent characterization of the modulation of drug/toxicant induced hepatotoxicities in mice through disruption of either Nrf2 or Keap1 genes. In general, loss of Nrf2 increases the sensitivity to such toxic chemicals, highlighting a central role of this transcription factor and its downstream target genes as a modifier to chemical stress. In this review, we summarize the impact of Nrf2 on the toxicology of multiple hepatotoxicants, and discuss efforts to utilize the Nrf2 response in predictive toxicology.


Nrf2 Keap1 Hepatoxicity Hepatocarcinogenesis Xenobiotic metabolism 



This work was supported by funding from MEXT/JSPS KAKENHI (16H01190 to K.T.); TERUMO LIFE SCIENCES FOUNDATION (18-III415 to K.T.) as well as NIH Grant R35 CA197222 (T.W.K) and the Washington State Andy Hill CARE Fund (T.W.K.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Alam J, Shibahara S, Smith A (1989) Transcriptional activation of the heme oxygenase gene by heme and cadmium in mouse hepatoma cells. J Biol Chem 264:6371–6375PubMedGoogle Scholar
  2. Ansher SS, Dolan P, Bueding E (1983) Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity. Hepatology 3:932–935PubMedCrossRefGoogle Scholar
  3. Anstee QM, Goldin RD (2006) Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 87:1–16PubMedPubMedCentralCrossRefGoogle Scholar
  4. Benson AM, Batzinger RP, Ou SY, Bueding E, Cha YN, Talalay P (1978) Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites of benzo(a)pyrene by dietary antioxidants. Cancer Res 38:4486–4495PubMedGoogle Scholar
  5. Benson AM, Hunkeler MJ, Talalay P (1980) Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. Proc Natl Acad Sci USA 77:5216–5220PubMedCrossRefGoogle Scholar
  6. Beyer TA, Xu W, Teupser D, auf dem Keller U, Bugnon P, Hildt E, Thiery J, Kan YW, Werner S (2008) Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance. EMBO J 27:212–223PubMedCrossRefGoogle Scholar
  7. Beyersmann D, Hechtenberg S (1997) Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol 144:247–261PubMedCrossRefGoogle Scholar
  8. Blake DJ, Singh A, Kombairaju P, Malhotra D, Mariani TJ, Tuder RM, Gabrielson E, Biswal S (2010) Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation. Am J Respir Cell Mol Biol 42:524–536PubMedCrossRefGoogle Scholar
  9. Botta D, White CC, Vliet-Gregg P, Mohar I, Shi S, McGrath MB, McConnachie LA, Kavanagh TJ (2008) Modulating GSH synthesis using glutamate cysteine ligase transgenic and gene-targeted mice. Drug Metab Rev 40:465–477PubMedCrossRefGoogle Scholar
  10. Chan K, Kan YW (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA 96:12731–12736PubMedCrossRefGoogle Scholar
  11. Chan K, Lu R, Chang JC, Kan YW (1996) NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci USA 93:13943–13948PubMedCrossRefGoogle Scholar
  12. Chan K, Han XD, Kan YW (2001) An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci USA 98:4611–4616PubMedCrossRefGoogle Scholar
  13. Chen HW, Huang YJ, Yao HT, Lii CK (2012) Induction of Nrf2-dependent antioxidation and protection against carbon tetrachloride-induced liver damage by Andrographis Herba (chuan xin lian) ethanolic extract. J Tradit Complement Med 2:211–219PubMedPubMedCentralCrossRefGoogle Scholar
  14. Chen S, Zou L, Li L, Wu T (2013) The protective effect of glycyrrhetinic acid on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. PLoS ONE 8:e53662PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cho BO, Ryu HW, Jin CH, Choi DS, Kang SY, Kim DS, Byun MW, Jeong IY (2011) Blackberry extract attenuates oxidative stress through up-regulation of Nrf2-dependent antioxidant enzymes in carbon tetrachloride-treated rats. J Agric Food Chem 59:11442–11448PubMedCrossRefGoogle Scholar
  16. Chowdhry S, Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T, Dillon JF, Ashford ML, Hayes JD (2010) Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic Biol Med 48:357–371PubMedCrossRefGoogle Scholar
  17. Chowdhry S, Zhang Y, McMahon M, Sutherland C, Cuadrado A, Hayes JD (2013) Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32:3765–3781PubMedCrossRefGoogle Scholar
  18. Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, Tan TX, Wu MC, Getz G, Lawrence MS, Parker JS, Li J, Powers S, Kim H, Fischer S, Guindi M, Ghanekar A, Chiang DY (2013) Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology 58:1693–1702PubMedPubMedCentralCrossRefGoogle Scholar
  19. Copple IM, den Hollander W, Callegaro G, Mutter FE, Maggs JL, Schofield AL, Rainbow L, Fang Y, Sutherland JJ, Ellis EC, Ingelman-Sundberg M, Fenwick SW, Goldring CE, van de Water B, Stevens JL, Park BK (2019) Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury. Arch Toxicol 93:385–399PubMedCrossRefGoogle Scholar
  20. Crawford DR, Ilic Z, Guest I, Milne GL, Hayes JD, Sell S (2017) Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice. Carcinogenesis 38:717–727PubMedPubMedCentralCrossRefGoogle Scholar
  21. Croquelois A, Blindenbacher A, Terracciano L, Wang X, Langer I, Radtke F, Heim MH (2005) Inducible inactivation of Notch1 causes nodular regenerative hyperplasia in mice. Hepatology 41:487–496PubMedCrossRefGoogle Scholar
  22. Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, Attucks OC, Franklin S, Levonen AL, Kensler TW, Dinkova-Kostova AT (2019) Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 18:295–317PubMedCrossRefGoogle Scholar
  23. Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81:1327–1331PubMedCrossRefGoogle Scholar
  24. Dhakshinamoorthy S, Jaiswal AK (2001) Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 20:3906–3917PubMedCrossRefGoogle Scholar
  25. Dinkova-Kostova AT, Fahey JW, Kostov RV, Kensler TW (2017) KEAP1 and done? Targeting the NRF2 pathway with sulforaphane. Trends Food Sci Technol 69:257–269PubMedPubMedCentralCrossRefGoogle Scholar
  26. Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59:169–177PubMedCrossRefGoogle Scholar
  27. Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ (1995) Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268:722–726PubMedCrossRefGoogle Scholar
  28. Fragoulis A, Schenkel J, Herzog M, Schellenberg T, Jahr H, Pufe T, Trautwein C, Kensler TW, Streetz KL, Wruck CJ (2019) Nrf2 ameliorates DDC-induced sclerosing cholangitis and biliary fibrosis and improves the regenerative capacity of the liver. Toxicol Sci 169:485–498PubMedCrossRefGoogle Scholar
  29. Friling RS, Bensimon A, Tichauer Y, Daniel V (1990) Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Natl Acad Sci USA 87:6258–6262PubMedCrossRefGoogle Scholar
  30. Friling RS, Bergelson S, Daniel V (1992) Two adjacent AP-1-like binding sites form the electrophile-responsive element of the murine glutathione S-transferase Ya subunit gene. Proc Natl Acad Sci USA 89:668–672PubMedCrossRefGoogle Scholar
  31. Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, Radtke F, Schmid RM, Siveke JT (2008) Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 48:607–616PubMedCrossRefGoogle Scholar
  32. Gong P, Cederbaum AI (2006) Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1. Hepatology 43:144–153PubMedCrossRefGoogle Scholar
  33. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clement B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouze E, Calvo F, Zucman-Rossi J (2012) Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 44:694–698PubMedPubMedCentralCrossRefGoogle Scholar
  34. Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113:1774–1783PubMedPubMedCentralCrossRefGoogle Scholar
  35. Huang R, Xia M, Sakamuru S, Zhao J, Shahane SA, Attene-Ramos M, Zhao T, Austin CP, Simeonov A (2016) Modelling the Tox21 10 K chemical profiles for in vivo toxicity prediction and mechanism characterization. Nat Commun 7:10425PubMedPubMedCentralCrossRefGoogle Scholar
  36. Itoh K, Igarashi K, Hayashi N, Nishizawa M, Yamamoto M (1995) Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol Cell Biol 15:4184–4193PubMedPubMedCentralCrossRefGoogle Scholar
  37. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322PubMedCrossRefPubMedCentralGoogle Scholar
  38. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86PubMedPubMedCentralCrossRefGoogle Scholar
  39. Johnson NM, Egner PA, Baxter VK, Sporn MB, Wible RS, Sutter TR, Groopman JD, Kensler TW, Roebuck BD (2014) Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold. Cancer Prev Res (Phila) 7:658–665CrossRefGoogle Scholar
  40. Kensler TW, Wakabayashi N (2010) Nrf2: friend or foe for chemoprevention? Carcinogenesis 31:90–99PubMedCrossRefGoogle Scholar
  41. Kensler TW, Egner PA, Trush MA, Bueding E, Groopman JD (1985) Modification of aflatoxin B1 binding to DNA in vivo in rats fed phenolic antioxidants, ethoxyquin and a dithiothione. Carcinogenesis 6:759–763PubMedCrossRefGoogle Scholar
  42. Kensler TW, Roebuck BD, Wogan GN, Groopman JD (2011) Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicol Sci 120(Suppl 1):S28–48PubMedCrossRefGoogle Scholar
  43. Kensler KH, Slocum SL, Chartoumpekis DV, Dolan PM, Johnson NM, Ilic Z, Crawford DR, Sell S, Groopman JD, Kensler TW, Egner PA (2014) Genetic or pharmacologic activation of Nrf2 signaling fails to protect against aflatoxin genotoxicity in hypersensitive GSTA3 knockout mice. Toxicol Sci 139:293–300PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kim DW, Cho HI, Kim KM, Kim SJ, Choi JS, Kim YS, Lee SM (2012) Isorhamnetin-3-O-galactoside protects against CCl4-induced hepatic injury in mice. Biomol Ther (Seoul) 20:406–412CrossRefGoogle Scholar
  45. Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H (2016) Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634–641PubMedCrossRefGoogle Scholar
  46. Kitteringham NR, Abdullah A, Walsh J, Randle L, Jenkins RE, Sison R, Goldring CE, Powell H, Sanderson C, Williams S, Higgins L, Yamamoto M, Hayes J, Park BK (2010) Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver. J Proteomics 73:1612–1631PubMedPubMedCentralCrossRefGoogle Scholar
  47. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139PubMedPubMedCentralCrossRefGoogle Scholar
  48. Kolonel LN (1976) Association of cadmium with renal cancer. Cancer 37:1782–1787PubMedCrossRefGoogle Scholar
  49. Kwak MK, Itoh K, Yamamoto M, Sutter TR, Kensler TW (2001) Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol Med 7:135–145PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278:8135–8145PubMedCrossRefGoogle Scholar
  51. Lahvis GP, Lindell SL, Thomas RS, McCuskey RS, Murphy C, Glover E, Bentz M, Southard J, Bradfield CA (2000) Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc Natl Acad Sci USA 97:10442–10447PubMedCrossRefGoogle Scholar
  52. Lahvis GP, Pyzalski RW, Glover E, Pitot HC, McElwee MK, Bradfield CA (2005) The aryl hydrocarbon receptor is required for developmental closure of the ductus venosus in the neonatal mouse. Mol Pharmacol 67:714–720PubMedCrossRefGoogle Scholar
  53. Laine JE, Auriola S, Pasanen M, Juvonen RO (2009) Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica 39:11–21PubMedCrossRefGoogle Scholar
  54. Lamle J, Marhenke S, Borlak J, von Wasielewski R, Eriksson CJ, Geffers R, Manns MP, Yamamoto M, Vogel A (2008) Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134:1159–1168PubMedCrossRefGoogle Scholar
  55. Lee HS, Li L, Kim HK, Bilehal D, Li W, Lee DS, Kim YH (2010) The protective effects of Curcuma longa Linn. extract on carbon tetrachloride-induced hepatotoxicity in rats via upregulation of Nrf2. J Microbiol Biotechnol 20:1331–1338PubMedCrossRefGoogle Scholar
  56. Li B, Wang L, Lu Q, Da W (2016) Liver injury attenuation by curcumin in a rat NASH model: an Nrf2 activation-mediated effect? Ir J Med Sci 185:93–100PubMedCrossRefGoogle Scholar
  57. Ma Q, Kinneer K, Bi Y, Chan JY, Kan YW (2004) Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap ‘n’ collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. Biochem J 377:205–213PubMedPubMedCentralCrossRefGoogle Scholar
  58. Machado MV, Michelotti GA, Xie G, Almeida Pereira T, Boursier J, Bohnic B, Guy CD, Diehl AM (2015) Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS ONE 10:e0127991PubMedPubMedCentralCrossRefGoogle Scholar
  59. Miao W, Hu L, Scrivens PJ, Batist G (2005) Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. J Biol Chem 280:20340–20348PubMedCrossRefGoogle Scholar
  60. Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M, Fujii-Kuriyama Y (1997) Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells 2:645–654PubMedCrossRefGoogle Scholar
  61. Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 187:185–194PubMedGoogle Scholar
  62. Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 91:9926–9930PubMedCrossRefGoogle Scholar
  63. Ngo HKC, Kim DH, Cha YN, Na HK, Surh YJ (2017) Nrf2 mutagenic activation drives hepatocarcinogenesis. Cancer Res 77:4797–4808PubMedCrossRefGoogle Scholar
  64. Noda S, Harada N, Hida A, Fujii-Kuriyama Y, Motohashi H, Yamamoto M (2003) Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse. Biochem Biophys Res Commun 303:105–111PubMedCrossRefGoogle Scholar
  65. Okada K, Warabi E, Sugimoto H, Horie M, Tokushige K, Ueda T, Harada N, Taguchi K, Hashimoto E, Itoh K, Ishii T, Utsunomiya H, Yamamoto M, Shoda J (2012) Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis. J Gastroenterol 47:924–935PubMedCrossRefGoogle Scholar
  66. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler TW, Yamamoto M (2006) Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun 339:79–88PubMedCrossRefGoogle Scholar
  67. Orru C, Szydlowska M, Taguchi K, Zavattari P, Perra A, Yamamoto M, Columbano A (2018) Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis. J Hepatol 69:635–643PubMedCrossRefGoogle Scholar
  68. Osburn WO, Yates MS, Dolan PD, Chen S, Liby KT, Sporn MB, Taguchi K, Yamamoto M, Kensler TW (2008) Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci 104:218–227PubMedPubMedCentralCrossRefGoogle Scholar
  69. Petersen DR, Saba LM, Sayin VI, Papagiannakopoulos T, Schmidt EE, Merrill GF, Orlicky DJ, Shearn CT (2018) Elevated Nrf-2 responses are insufficient to mitigate protein carbonylation in hepatospecific PTEN deletion mice. PLoS ONE 13:e0198139PubMedPubMedCentralCrossRefGoogle Scholar
  70. Piscator M (1981) Role of cadmium in carcinogenesis with special reference to cancer of the prostate. Environ Health Perspect 40:107–120PubMedPubMedCentralCrossRefGoogle Scholar
  71. Prestera T, Zhang Y, Spencer SR, Wilczak CA, Talalay P (1993) The electrophile counterattack response: protection against neoplasia and toxicity. Adv Enzyme Regul 33:281–296PubMedCrossRefGoogle Scholar
  72. Priestley JR, Kautenburg KE, Casati MC, Endres BT, Geurts AM, Lombard JH (2016) The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction. Am J Physiol Heart Circ Physiol 310:H478–487PubMedCrossRefGoogle Scholar
  73. Primiano T, Gastel JA, Kensler TW, Sutter TR (1996) Isolation of cDNAs representing dithiolethione-responsive genes. Carcinogenesis 17:2297–2303PubMedCrossRefGoogle Scholar
  74. Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, Kensler TW (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98:3410–3415PubMedCrossRefGoogle Scholar
  75. Ramos-Tovar E, Hernandez-Aquino E, Casas-Grajales S, Buendia-Montano LD, Galindo-Gomez S, Camacho J, Tsutsumi V, Muriel P (2018) Stevia prevents acute and chronic liver injury induced by carbon tetrachloride by blocking oxidative stress through Nrf2 upregulation. Oxid Med Cell Longev 2018:3823426PubMedPubMedCentralCrossRefGoogle Scholar
  76. Randle LE, Goldring CE, Benson CA, Metcalfe PN, Kitteringham NR, Park BK, Williams DP (2008) Investigation of the effect of a panel of model hepatotoxins on the Nrf2-Keap1 defence response pathway in CD-1 mice. Toxicology 243:249–260PubMedCrossRefGoogle Scholar
  77. Reisman SA, Buckley DB, Tanaka Y, Klaassen CD (2009) CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes. Toxicol Appl Pharmacol 236:109–114PubMedPubMedCentralCrossRefGoogle Scholar
  78. Room R, Babor T, Rehm J (2005) Alcohol and public health. Lancet 365:519–530PubMedCrossRefGoogle Scholar
  79. Rooney J, Oshida K, Vasani N, Vallanat B, Ryan N, Chorley BN, Wang X, Bell DA, Wu KC, Aleksunes LM, Klaassen CD, Kensler TW, Corton JC (2018) Activation of Nrf2 in the liver is associated with stress resistance mediated by suppression of the growth hormone-regulated STAT5b transcription factor. PLoS ONE 13:e0200004PubMedPubMedCentralCrossRefGoogle Scholar
  80. Rudolph TK, Freeman BA (2009) Transduction of redox signaling by electrophile-protein reactions. Sci Signal 2:re7PubMedPubMedCentralCrossRefGoogle Scholar
  81. Rushmore TH, Pickett CB (1990) Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem 265:14648–14653PubMedGoogle Scholar
  82. Rushmore TH, Morton MR, Pickett CB (1991) The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266:11632–11639PubMedGoogle Scholar
  83. Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T, Motohashi H, Waguri S, Soga T, Yamamoto M, Tanaka K, Komatsu M (2016) p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun 7:12030PubMedPubMedCentralCrossRefGoogle Scholar
  84. Sekhar KR, Yan XX, Freeman ML (2002) Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. Oncogene 21:6829–6834PubMedCrossRefGoogle Scholar
  85. Sharma RS, Harrison DJ, Kisielewski D, Cassidy DM, McNeilly AD, Gallagher JR, Walsh SV, Honda T, McCrimmon RJ, Dinkova-Kostova AT, Ashford MLJ, Dillon JF, Hayes JD (2018) Experimental nonalcoholic steatohepatitis and liver fibrosis are ameliorated by pharmacologic activation of Nrf2 (NF-E2 p45-related factor 2). Cell Mol Gastroenterol Hepatol 5:367–398PubMedCrossRefGoogle Scholar
  86. Shimozono R, Asaoka Y, Yoshizawa Y, Aoki T, Noda H, Yamada M, Kaino M, Mochizuki H (2013) Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model. Mol Pharmacol 84:62–70PubMedCrossRefGoogle Scholar
  87. Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, Yamamoto M, Kensler TW (2007) NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol 27:7188–7197PubMedPubMedCentralCrossRefGoogle Scholar
  88. Shukla SJ, Huang R, Simmons SO, Tice RR, Witt KL, Vanleer D, Ramabhadran R, Austin CP, Xia M (2012) Profiling environmental chemicals for activity in the antioxidant response element signaling pathway using a high throughput screening approach. Environ Health Perspect 120:1150–1156PubMedPubMedCentralCrossRefGoogle Scholar
  89. Skoko JJ, Wakabayashi N, Noda K, Kimura S, Tobita K, Shigemura N, Tsujita T, Yamamoto M, Kensler TW (2014) Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity. Toxicol Sci 141:112–119PubMedPubMedCentralCrossRefGoogle Scholar
  90. Solt DB, Medline A, Farber E (1977) Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis. Am J Pathol 88:595–618PubMedPubMedCentralGoogle Scholar
  91. Stephenson K, Kennedy L, Hargrove L, Demieville J, Thomson J, Alpini G, Francis H (2018) Updates on dietary models of nonalcoholic fatty liver disease: current studies and insights. Gene Expr 18:5–17PubMedPubMedCentralCrossRefGoogle Scholar
  92. Stewart D, Killeen E, Naquin R, Alam S, Alam J (2003) Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J Biol Chem 278:2396–2402PubMedCrossRefGoogle Scholar
  93. Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, Ueda T, Taguchi K, Yanagawa T, Nakahara A, Hyodo I, Ishii T, Yamamoto M (2010) Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 298:G283–294PubMedCrossRefGoogle Scholar
  94. Sun J, Fu J, Zhong Y, Li L, Chen C, Wang X, Wang L, Hou Y, Wang H, Zhao R, Zhang X, Yamamoto M, Xu Y, Pi J (2018) NRF2 mitigates acute alcohol-induced hepatic and pancreatic injury in mice. Food Chem Toxicol 121:495–503PubMedCrossRefGoogle Scholar
  95. Taguchi K, Maher JM, Suzuki T, Kawatani Y, Motohashi H, Yamamoto M (2010) Genetic analysis of cytoprotective functions supported by graded expression of Keap1. Mol Cell Biol 30:3016–3026PubMedPubMedCentralCrossRefGoogle Scholar
  96. Taguchi K, Hirano I, Itoh T, Tanaka M, Miyajima A, Suzuki A, Motohashi H, Yamamoto M (2014) Nrf2 enhances cholangiocyte expansion in Pten-deficient livers. Mol Cell Biol 34:900–913PubMedPubMedCentralCrossRefGoogle Scholar
  97. Taguchi K, Takaku M, Egner PA, Morita M, Kaneko T, Mashimo T, Kensler TW, Yamamoto M (2016) Generation of a new model rat: Nrf2 knockout rats are sensitive to aflatoxin B1 toxicity. Toxicol Sci 152:40–52PubMedPubMedCentralCrossRefGoogle Scholar
  98. Taguchi K, Masui S, Itoh T, Miyajima A, Yamamoto M (2019) Nrf2 activation ameliorates hepatotoxicity induced by a heme synthesis inhibitor. Toxicol Sci 167:227–238PubMedCrossRefGoogle Scholar
  99. Talalay P, De Long MJ, Prochaska HJ (1988) Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci USA 85:8261–8265PubMedCrossRefGoogle Scholar
  100. Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT, Hayes JD (2015) Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med 88:108–146PubMedPubMedCentralCrossRefGoogle Scholar
  101. Tice RR, Austin CP, Kavlock RJ, Bucher JR (2013) Improving the human hazard characterization of chemicals: a Tox21 update. Environ Health Perspect 121:756–765PubMedPubMedCentralCrossRefGoogle Scholar
  102. Tiegs G, Hentschel J, Wendel A (1992) A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest 90:196–203PubMedPubMedCentralCrossRefGoogle Scholar
  103. Ushida Y, Talalay P (2013) Sulforaphane accelerates acetaldehyde metabolism by inducing aldehyde dehydrogenases: relevance to ethanol intolerance. Alcohol Alcohol 48:526–534PubMedCrossRefGoogle Scholar
  104. Verna L, Whysner J, Williams GM (1996) N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther 71:57–81PubMedCrossRefGoogle Scholar
  105. Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, Imakado S, Kotsuji T, Otsuka F, Roop DR, Harada T, Engel JD, Yamamoto M (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35:238–245PubMedCrossRefGoogle Scholar
  106. Wakabayashi N, Shin S, Slocum SL, Agoston ES, Wakabayashi J, Kwak MK, Misra V, Biswal S, Yamamoto M, Kensler TW (2010a) Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci Signal 3:ra52PubMedPubMedCentralCrossRefGoogle Scholar
  107. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW (2010b) When NRF2 talks, who’s listening? Antioxid Redox Signal 13:1649–1663PubMedPubMedCentralCrossRefGoogle Scholar
  108. Wakabayashi N, Skoko JJ, Chartoumpekis DV, Kimura S, Slocum SL, Noda K, Palliyaguru DL, Fujimuro M, Boley PA, Tanaka Y, Shigemura N, Biswal S, Yamamoto M, Kensler TW (2014) Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling. Mol Cell Biol 34:653–663PubMedPubMedCentralCrossRefGoogle Scholar
  109. Walsh J, Jenkins RE, Wong M, Olayanju A, Powell H, Copple I, O’Neill PM, Goldring CE, Kitteringham NR, Park BK (2014) Identification and quantification of the basal and inducible Nrf2-dependent proteomes in mouse liver: biochemical, pharmacological and toxicological implications. J Proteomics 108:171–187PubMedPubMedCentralCrossRefGoogle Scholar
  110. Wang W, He Y, Yu G, Li B, Sexton DW, Wileman T, Roberts AA, Hamilton CJ, Liu R, Chao Y, Shan Y, Bao Y (2015) Sulforaphane protects the liver against CdSe quantum dot-induced cytotoxicity. PLoS ONE 10:e0138771PubMedPubMedCentralCrossRefGoogle Scholar
  111. Wible RS, Tran QT, Fathima S, Sutter CH, Kensler TW, Sutter TR (2018) Pharmacogenomics of chemically distinct classes of Keap1-Nrf2 activators identify common and unique gene, protein, and pathway responses in v ivo. Mol Pharmacol 93:297–308PubMedPubMedCentralCrossRefGoogle Scholar
  112. Wu KC, Cui JY, Klaassen CD (2012a) Effect of graded Nrf2 activation on phase-I and -II drug metabolizing enzymes and transporters in mouse liver. PLoS ONE 7:e39006PubMedPubMedCentralCrossRefGoogle Scholar
  113. Wu KC, Liu J, Klaassen CD (2012b) Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation. Toxicol Appl Pharmacol 262:321–329PubMedCrossRefGoogle Scholar
  114. Xia M, Huang R, Shi Q, Boyd WA, Zhao J, Sun N, Rice JR, Dunlap PE, Hackstadt AJ, Bridge MF, Smith MV, Dai S, Zheng W, Chu PH, Gerhold D, Witt KL, DeVito M, Freedman JH, Austin CP, Houck KA, Thomas RS, Paules RS, Tice RR, Simeonov A (2018) Comprehensive analyses and prioritization of Tox21 10 K chemicals affecting mitochondrial function by in-depth mechanistic studies. Environ Health Perspect 126:077010PubMedPubMedCentralCrossRefGoogle Scholar
  115. Xu W, Hellerbrand C, Kohler UA, Bugnon P, Kan YW, Werner S, Beyer TA (2008) The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis. Lab Invest 88:1068–1078PubMedCrossRefGoogle Scholar
  116. Xue P, Hou Y, Chen Y, Yang B, Fu J, Zheng H, Yarborough K, Woods CG, Liu D, Yamamoto M, Zhang Q, Andersen ME, Pi J (2013) Adipose deficiency of Nrf2 in ob/ob mice results in severe metabolic syndrome. Diabetes 62:845–854PubMedPubMedCentralCrossRefGoogle Scholar
  117. Yamamoto M, Kensler TW, Motohashi H (2018) The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 98:1169–1203PubMedCrossRefGoogle Scholar
  118. Yanagawa T, Itoh K, Uwayama J, Shibata Y, Yamaguchi A, Sano T, Ishii T, Yoshida H, Yamamoto M (2004) Nrf2 deficiency causes tooth decolourization due to iron transport disorder in enamel organ. Genes Cells 9:641–651PubMedCrossRefGoogle Scholar
  119. Yates MS, Kwak M-K, Egner PA, Groopman JD, Bodreddigari S, Sutter TR, Baumgartner KJ, Roebuck BD, Yore MM, Honda T, Gribble GW, Sporn MB, Kensler TW (2006) Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res 66:2488–2494PubMedCrossRefGoogle Scholar
  120. Yates MS, Tran QT, Dolan PM, Osburn WO, Shin S, McCulloch CC, Silkworth JB, Taguchi K, Yamamoto M, Williams CR, Liby KT, Sporn MB, Sutter TR, Kensler TW (2009) Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis 30:1024–1031PubMedPubMedCentralCrossRefGoogle Scholar
  121. Yoo NJ, Kim HR, Kim YR, An CH, Lee SH (2012) Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology 60:943–952PubMedCrossRefGoogle Scholar
  122. Zavattari P, Perra A, Menegon S, Kowalik MA, Petrelli A, Angioni MM, Follenzi A, Quagliata L, Ledda-Columbano GM, Terracciano L, Giordano S, Columbano A (2015) Nrf2, but not beta-catenin, mutation represents an early event in rat hepatocarcinogenesis. Hepatology 62:851–862PubMedCrossRefGoogle Scholar
  123. Zhao M, Chen J, Zhu P, Fujino M, Takahara T, Toyama S, Tomita A, Zhao L, Yang Z, Hei M, Zhong L, Zhuang J, Kimura S, Li XK (2015) Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells. Int Immunopharmacol 28:938–944PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Medical Biochemistry, Graduate School of MedicineTohoku UniversityAobaJapan
  2. 2.Fred Hutchinson Cancer Research CenterSeattleUSA

Personalised recommendations