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

Abstract

Nrf2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions. Germ line deletion of the keap1 gene results in constitutive activation of Nrf2, but the pups unexpectedly died before weaning. To investigate how constitutive activation of Nrf2 influences the detoxification system in adult mice, we generated mice bearing a hepatocyte-specific disruption of the keap1 gene. Homozygous mice were viable and their livers displayed no apparent abnormalities, but nuclear accumulation of Nrf2 is elevated. Microarray analysis revealed that, while many detoxifying enzyme genes are highly expressed, some of the typical Nrf2-dependent genes are only marginally increased in the Keap1-deficient liver. The mutant mice were significantly more resistant to toxic doses of acetaminophen than control animals. These results demonstrate that chronic activation of Nrf2 confers animals with resistance to xenobiotics without affecting the morphological and physiological integrity of hepatocytes.

Authors:
 [1];  [1];  [1];  [2];  [3];  [4]
  1. Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577 (Japan)
  2. Research Center for Advance Science and Technology, University of Tokyo, Tokyo 153-8904 (Japan)
  3. Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205 (United States)
  4. Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577 (Japan) and ERATO Environmental Response Project, Japan Science and Technology Corporation, 1-1-1 Tennoudai, Tsukuba 305-8577 (Japan)
Publication Date:
OSTI Identifier:
20795850
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 339; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2005.10.185; PII: S0006-291X(05)02473-3; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DETOXIFICATION; DRUGS; ENZYMES; GENES; KNOCK-OUT REACTIONS; LIVER; LIVER CELLS; MICE; MUTANTS; TOXICITY; XENOBIOTICS

Citation Formats

Okawa, Hiromi, Motohashi, Hozumi, Kobayashi, Akira, Aburatani, Hiroyuki, Kensler, Thomas W, and Yamamoto, Masayuki. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. United States: N. p., 2006. Web. doi:10.1016/J.BBRC.2005.1.
Okawa, Hiromi, Motohashi, Hozumi, Kobayashi, Akira, Aburatani, Hiroyuki, Kensler, Thomas W, & Yamamoto, Masayuki. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. United States. https://doi.org/10.1016/J.BBRC.2005.1
Okawa, Hiromi, Motohashi, Hozumi, Kobayashi, Akira, Aburatani, Hiroyuki, Kensler, Thomas W, and Yamamoto, Masayuki. 2006. "Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity". United States. https://doi.org/10.1016/J.BBRC.2005.1.
@article{osti_20795850,
title = {Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity},
author = {Okawa, Hiromi and Motohashi, Hozumi and Kobayashi, Akira and Aburatani, Hiroyuki and Kensler, Thomas W and Yamamoto, Masayuki},
abstractNote = {Nrf2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions. Germ line deletion of the keap1 gene results in constitutive activation of Nrf2, but the pups unexpectedly died before weaning. To investigate how constitutive activation of Nrf2 influences the detoxification system in adult mice, we generated mice bearing a hepatocyte-specific disruption of the keap1 gene. Homozygous mice were viable and their livers displayed no apparent abnormalities, but nuclear accumulation of Nrf2 is elevated. Microarray analysis revealed that, while many detoxifying enzyme genes are highly expressed, some of the typical Nrf2-dependent genes are only marginally increased in the Keap1-deficient liver. The mutant mice were significantly more resistant to toxic doses of acetaminophen than control animals. These results demonstrate that chronic activation of Nrf2 confers animals with resistance to xenobiotics without affecting the morphological and physiological integrity of hepatocytes.},
doi = {10.1016/J.BBRC.2005.1},
url = {https://www.osti.gov/biblio/20795850}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 339,
place = {United States},
year = {Fri Jan 06 00:00:00 EST 2006},
month = {Fri Jan 06 00:00:00 EST 2006}
}