Constitutive activation of nuclear factor-E2-related factor 2 induces biotransformation enzyme and transporter expression in livers of mice with hepatocyte-specific deletion of Kelch-like ECH-associated protein 1

Qiuqiong Cheng, Keiko Taguchi, Lauren M. Aleksunes, José E. Manautou, Nathan J. Cherrington, Masayuki Yamamoto, Angela L. Slitt

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Chemicals that activate nuclear factor-E2-related factor 2 (Nrf2) often increase multidrug-resistance-associated protein (Mrp) expression in liver. Hepatocyte-specific deletion of Kelch-like ECH-associated protein 1 (Keap1) activates Nrf2. Use of hepatocyte-specific Keap1 deletion represents a nonpharmacological method to determine whether constitutive Nrf2 activation upregulates liver transporter expression in vivo. The mRNA, protein expression, and localization of several biotransformation and transporters were determined in livers of wild-type and hepatocyte-specific Keap1-null mice. Sulfotransferase 2a1/2, NADP(H):quinone oxidoreductase 1, cytochrome P450 2b10, 3a11, and glutamate-cysteine ligase catalytic subunit expression were increased in livers of Keap1-null mice. Organic anion-transporting polypeptide 1a1 expression was nearly abolished, as compared to that detected in livers of wild-type mice. By contrast, Mrp 1-5 mRNA and protein levels were increased in Keap1-null mouse livers, with Mrp4 expression being more than 15-fold higher than wild types. In summary, Nrf2 has a significant role in affecting Oatp and Mrp expressions.

Original languageEnglish (US)
Pages (from-to)320-329
Number of pages10
JournalJournal of Biochemical and Molecular Toxicology
Volume25
Issue number5
DOIs
StatePublished - Sep 2011

Keywords

  • Abcc4
  • Kelch-Like ECH-Associated Protein 1(Kea-p1)
  • Multidrug-Resistance-Associated Protein(Mrp)
  • Nfe2Lz) Organic Anion-Transporting Polypeptide (Oatp)
  • Nuclear Factor-E2-Related Factor 2(nrfz

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Toxicology
  • Health, Toxicology and Mutagenesis

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