Toxicological Sciences 59, 169-177 (2001)
Copyright © 2001 by the Society of Toxicology
Systems Toxicology |
High Sensitivity of Nrf2 Knockout Mice to Acetaminophen Hepatotoxicity Associated with Decreased Expression of ARE-Regulated Drug Metabolizing Enzymes and Antioxidant Genes
* Toxicology Division II, Laboratory of Pathology, Institute of Environmental Toxicology, 4321 Uchimoriya, Mitsukaido, Ibaraki 303-0043, Japan;
Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan; and
Chemistry Division, Institute of Environmental Toxicology, 4321 Uchimoriya, Mitsukaido, Ibaraki 303-0043, Japan
Nrf2, which belongs to the basic leucine zipper (bZip) transcription factor family, has been implicated as a key molecule involved in antioxidant-responsive element (ARE)-mediated gene expression. In order to examine the role of Nrf2 in protection against xenobiotic toxicity, the sensitivity of nrf2 knockout mice to acetaminophen (N-acetyl-4-aminophenol (APAP)) was analyzed. The saturation of detoxification pathways after high levels of exposure to APAP is known to induce hepatotoxicity. Two factors important in its detoxification are UDP-glucuronosyltransferase (UDP-GT), an ARE-regulated phase-II drug-metabolizing enzyme, and glutathione (GSH), an antioxidant molecule whose synthesis depends on ARE-regulated 
-glutamylcysteine synthetase (GCS). Two- to 4-month-old male mice were orally administered a single dose of APAP at 0, 150, 300, or 600 mg/kg. Doses of 300 mg/kg APAP or greater caused death in the homozygous knockout mice only, and those that survived showed a greater severity in hepatic damage than the wild-type mice, as demonstrated by increased plasma alanine aminotransferase activity, decreased hepatic non-protein sulfhydryl (NPSH) content, and centrilobular hepatocellular necrosis. The high sensitivity of Nrf2-deficient mice was confirmed from observations made at 0, 2, 8, and 24 h after dosing with 300 mg/kg APAP; increased anti-APAP immunoreactivity was also noted in their livers at 2 h. Untreated homozygous knockout mice showed both a lower UDP-GT activity and NPSH content, which corresponded to decreased mRNA levels of UDP-GT (Ugt1a6) and the heavy chain of GCS, respectively. These results show that Nrf2 plays a protective role against APAP hepatotoxicity by regulating both drug metabolizing enzymes and antioxidant genes through the ARE.
Key Words: Nrf2; knockout mice; acetaminophen; hepatotoxicity; ARE; oxidative stress; electrophile; UDP-glucuronosyltransferase; glutathione; -glutamylcysteine synthetase.
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R. K. Thimmulappa, K. H. Mai, S. Srisuma, T. W. Kensler, M. Yamamoto, and S. Biswal Identification of Nrf2-regulated Genes Induced by the Chemopreventive Agent Sulforaphane by Oligonucleotide Microarray Cancer Res., September 15, 2002; 62(18): 5196 - 5203. [Abstract] [Full Text] [PDF]
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A. T. Dinkova-Kostova, W. D. Holtzclaw, R. N. Cole, K. Itoh, N. Wakabayashi, Y. Katoh, M. Yamamoto, and P. Talalay Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants PNAS, September 3, 2002; 99(18): 11908 - 11913. [Abstract] [Full Text] [PDF]
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S. Braun, C. Hanselmann, M. G. Gassmann, U. auf dem Keller, C. Born-Berclaz, K. Chan, Y. W. Kan, and S. Werner Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound Mol. Cell. Biol., August 1, 2002; 22(15): 5492 - 5505. [Abstract] [Full Text] [PDF]
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M.-K. Kwak, K. Itoh, M. Yamamoto, and T. W. Kensler Enhanced Expression of the Transcription Factor Nrf2 by Cancer Chemopreventive Agents: Role of Antioxidant Response Element-Like Sequences in the nrf2 Promoter Mol. Cell. Biol., May 1, 2002; 22(9): 2883 - 2892. [Abstract] [Full Text] [PDF]
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 H.-Y. Cho, A. E. Jedlicka, S. P. M. Reddy, L.-Y. Zhang, T. W. Kensler, and S. R. Kleeberger Linkage Analysis of Susceptibility to Hyperoxia . Nrf2 Is a Candidate Gene Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 42 - 51. [Abstract] [Full Text] [PDF]
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M. Ramos-Gomez, M.-K. Kwak, P. M. Dolan, K. Itoh, M. Yamamoto, P. Talalay, and T. W. Kensler From the Cover: Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice PNAS, March 13, 2001; 98(6): 3410 - 3415. [Abstract] [Full Text] [PDF]
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J.-M. Lee, J. M. Hanson, W. A. Chu, and J. A. Johnson Phosphatidylinositol 3-Kinase, Not Extracellular Signal-regulated Kinase, Regulates Activation of the Antioxidant-Responsive Element in IMR-32 Human Neuroblastoma Cells J. Biol. Chem., June 1, 2001; 276(23): 20011 - 20016. [Abstract] [Full Text] [PDF]
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P. Gong, B. Hu, D. Stewart, M. Ellerbe, Y. G. Figueroa, V. Blank, B. S. Beckman, and J. Alam Cobalt Induces Heme Oxygenase-1 Expression by a Hypoxia-inducible Factor-independent Mechanism in Chinese Hamster Ovary Cells. REGULATION BY Nrf2 AND MafG TRANSCRIPTION FACTORS J. Biol. Chem., July 13, 2001; 276(29): 27018 - 27025. [Abstract] [Full Text] [PDF]
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