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Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal DiseaseDepartment of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA Correspondence: Address correspondence to: Dr. José E. Manautou, Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT 06269-3092, USA; e-mail:jose.manautou{at}uconn.edu
Transcription factor NF-E2-related factor 2 (Nrf2) belongs to the basic region-leucine zipper family and is activated in response to electrophiles and reactive oxygen species. Nrf2 coordinately regulates the constitutive and inducible transcription of a wide array of genes involved in drug metabolism, detoxification, and antioxidant defenses. During periods of oxidative stress, Nrf2 is released from sequestration in the cytoplasm and translocates to the nucleus. Nrf2 binds antioxidant response elements (AREs) in the regulatory regions of target genes and activates transcription. Genetically modified mice lacking Nrf2 serve as a useful tool for identifying new ARE-regulated genes and assessing the ability of Nrf2 to confer protection against a variety of pathologies in numerous organs including the liver, intestine, lung, skin, and nervous system. With regards to the liver and gastrointestinal tract, Nrf2 knockout mice are more susceptible to acetaminophen-induced hepatocellular injury, benzo[a]pyrene-induced tumor formation and Fas-and TNF
Key Words: Nrf2 • liver • gastrointestinal • ARE • Keap1 • oxidative stress Abbreviations: ACF, aberrant crypt foci • AOM, azoxymethane • AP-1, activator protein-1 • APAP, acetaminophen • ARE, antioxidant response element • bZIP, basic region-leucine zipper • β-NF, β-naphthoflavone • BHA, butylated hydroxyanisole • Carbamoyl-PROXYL, 3-carbamoyl-2, 2, 5, 5-tetramethylpyrrolidine-1-oxyl • CDDOIm, 1-[2-cyano-3-, 12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole • Cyp2E1, cytochrome P450 2E1 • D3T, 3H-1, 2-dithiol-3-thione • DGR, double glycine repeat • EpRE, electrophile response element • Gcl, glutamate-cysteine ligase • GI-GPx, glutathione peroxidase-gastrointestinal isoform • GSH, glutathione • GS, glutathione synthetase • Gst, glutathione-S-transferase • Ho-1, heme oxygenase-1 • Keap1, kelch-like ECH-associated protein 1 • Maf, musculo-aponeurotic fibrosarcoma • Mdr, multidrug resistance proteins • mEH, microsomal epoxide hydrolase • Mrp, multidrug resistance-associated proteins • Neh2, Nrf2-ECH homology 2 • NF-
Toxicologic Pathology, Vol. 35, No. 4,
459-473 (2007) This article has been cited by other articles:
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-mediated hepatocellular apoptosis. The higher sensitivity of Nrf2 knockout mice to chemical toxicity is due in part to reduced basal and inducible expression of detoxification enzymes. Nrf2 may also be important in protecting against liver fibrosis, gallstone development, and formation of aberrant crypt foci. Research of Nrf2 has opened up new opportunities in understanding how antioxidant defense pathways are regulated, how oxidative stress contributes to disease progression and may serve as a novel target for designing therapies to prevent and treat diseases in which oxidative stress is implicated. 
B, nuclear factor kappa B • Nqo1, NAD(P)H quinone oxidoreductase 1 • Nrf2, NF-E2 related factor 2 • PCP, pentachlorophenol • ROS, reactive oxygen species • PMA, phorbol 12-myristate 13-acetate • tBHQ, tert-butyl-hydroquinone • TNF
