Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin

Mol Pharmacol. 2017 Aug;92(2):113-123. doi: 10.1124/mol.117.108225. Epub 2017 May 25.

Abstract

CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA (4- to 15-fold) by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3, above 1.8-fold) and H3 acetylation (above 2-fold) and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3, about 50%) in the CYP3A4 promoter. Rifampicin enhanced recruitment to the CYP3A4 promoter of nuclear receptor coactivator 6 (NCOA6, above 3-fold) and histone acetyltransferase p300 (p300, above 1.6-fold). Silencing NCOA6 or p300 by short-hairpin RNAs resulted in inhibition of the CYP3A4 induction as well as altered levels of H3K4me3, H3K27me3, or H3 acetylation in the CYP3A4 promoter. Knockdown of pregnane X receptor (PXR) expression not only suppressed the recruitment of NCOA6 and p300 but also abolished the changes caused by rifampicin in H3K4me3, H3K27me3, and H3 acetylation levels in the CYP3A4 promoter. Moreover, rifampicin treatment enhanced the nuclear accumulation and interactions between PXR and NCOA6/p300. In conclusion, we show that the alterations of histone modifications contribute to the PXR-mediated induction of CYP3A4 by rifampicin.

MeSH terms

  • Cell Line, Tumor
  • Cytochrome P-450 CYP3A / biosynthesis*
  • Cytochrome P-450 CYP3A Inducers / pharmacology*
  • Epigenesis, Genetic / drug effects
  • Epigenesis, Genetic / physiology
  • Histones / metabolism*
  • Humans
  • Pregnane X Receptor
  • Receptors, Steroid / physiology*
  • Rifampin / pharmacology*

Substances

  • Cytochrome P-450 CYP3A Inducers
  • Histones
  • Pregnane X Receptor
  • Receptors, Steroid
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Rifampin