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

Hiromi Okawa, Hozumi Motohashi, Akira Kobayashi, Hiroyuki Aburatani, Thomas W. Kensler, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

286 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)79-88
Number of pages10
JournalBiochemical and biophysical research communications
Volume339
Issue number1
DOIs
Publication statusPublished - 2006 Jan 6
Externally publishedYes

Keywords

  • ARE
  • Acetaminophen
  • Alb-Cre
  • Conditional knockout mice
  • GST
  • Hepatotoxicity
  • Keap1
  • Nrf2
  • Phase2 enzymes
  • UGT

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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