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

J Biochem Mol Toxicol. 2011 Sep-Oct;25(5):320-9. doi: 10.1002/jbt.20392. Epub 2011 May 2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency*
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytoskeletal Proteins / deficiency*
  • Cytoskeletal Proteins / genetics
  • Drug Resistance, Multiple / genetics*
  • Gene Deletion
  • Gene Expression Regulation*
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • Liver / cytology
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism
  • Signal Transduction*

Substances

  • Abcc4 protein, mouse
  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Multidrug Resistance-Associated Proteins
  • NF-E2-Related Factor 2
  • Organic Anion Transporters
  • Cytochrome P-450 Enzyme System
  • NAD(P)H Dehydrogenase (Quinone)
  • Glutamate-Cysteine Ligase