Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver

Hepatology. 2012 Oct;56(4):1499-509. doi: 10.1002/hep.25766.

Abstract

Aberrant epigenetic alterations during development may result in long-term epigenetic memory and have a permanent effect on the health of subjects. Constitutive androstane receptor (CAR) is a central regulator of drug/xenobiotic metabolism. Here, we report that transient neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. CAR activation by neonatal exposure to the CAR-specific ligand 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) led to persistently induced expression of the CAR target genes Cyp2B10 and Cyp2C37 throughout the life of exposed mice. These mice showed a permanent reduction in sensitivity to zoxazolamine treatment as adults. Compared with control groups, the induction of Cyp2B10 and Cyp2C37 in hepatocytes isolated from these mice was more sensitive to low concentrations of the CAR agonist TCPOBOP. Accordingly, neonatal activation of CAR led to a permanent increase of histone 3 lysine 4 mono-, di-, and trimethylation and decrease of H3K9 trimethylation within the Cyp2B10 locus. Transcriptional coactivator activating signal cointegrator-2 and histone demethylase JMJD2d participated in this CAR-dependent epigenetic switch.

Conclusion: Neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • DNA Methylation
  • Disease Models, Animal
  • Epigenesis, Genetic / genetics
  • Epigenesis, Genetic / physiology*
  • Female
  • Gene Expression Regulation
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Liver / drug effects*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • RNA / metabolism
  • Random Allocation
  • Real-Time Polymerase Chain Reaction / methods
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Sensitivity and Specificity

Substances

  • Pyridines
  • Receptors, Cytoplasmic and Nuclear
  • constitutive androstane receptor
  • RNA
  • 1,4-bis(2-(3,5-dichloropyridyloxy))benzene