Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4

J Biol Chem. 2008 Apr 11;283(15):9674-80. doi: 10.1074/jbc.M709382200. Epub 2008 Feb 11.

Abstract

Pregnane X receptor (PXR) is a major transcription factor regulating the inducible expression of a variety of transporters and drug-metabolizing enzymes, including CYP3A4 (cytochrome P450 3A4). We first found that the PXR mRNA level was not correlated with the PXR protein level in a panel of 25 human livers, indicating the involvement of post-transcriptional regulation. Notably, a potential miR-148a recognition element was identified in the 3'-untranslated region of human PXR mRNA. We investigated whether PXR might be regulated by miR-148a. A reporter assay revealed that miR-148a could recognize the miR-148a recognition element of PXR mRNA. The PXR protein level was decreased by the overexpression of miR-148a, whereas it was increased by inhibition of miR-148a. The miR-148a-dependent decrease of PXR protein attenuated the induction CYP3A4 mRNA. Furthermore, the translational efficiency of PXR (PXR protein/PXR mRNA ratio) was inversely correlated with the expression levels of miR-148a in a panel of 25 human livers, supporting the miR-148a-dependent regulation of PXR in human livers. Eventually, the PXR protein level was significantly correlated with the CYP3A4 mRNA and protein levels. In conclusion, we found that miR-148a post-transcriptionally regulated human PXR, resulting in the modulation of the inducible and/or constitutive levels of CYP3A4 in human liver. This study will provide new insight into the unsolved mechanism of the large interindividual variability of CYP3A4 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • 3' Untranslated Regions / metabolism*
  • Caco-2 Cells
  • Cytochrome P-450 CYP3A / biosynthesis*
  • Cytochrome P-450 CYP3A / genetics
  • Gene Expression Regulation, Enzymologic / physiology*
  • Humans
  • Liver / enzymology*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Pregnane X Receptor
  • Protein Biosynthesis / physiology*
  • Receptors, Steroid / biosynthesis*
  • Receptors, Steroid / genetics

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • Pregnane X Receptor
  • Receptors, Steroid
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human