Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes

Biochem Biophys Res Commun. 2000 Aug 11;274(3):707-13. doi: 10.1006/bbrc.2000.3219.

Abstract

The marked impairment of hepatic drug metabolism during inflammation and infections has been known for many years and shown to result from down-regulation of cytochrome P450s (CYP) by cytokines. However, the mechanism of this repression is unknown. Using primary cultures of human hepatocytes, we show here that interleukin-6 (IL-6) rapidly and markedly decreases the expression of PXR (pregnane X receptor) and CAR (constitutively activated receptor) mRNAs, but does not affect the levels of dioxin receptor and glucocorticoid receptor mRNA. In parallel, IL-6 decreases both rifampicin- and phenobarbital-mediated induction of CYP2B6, CYP2C8, CYP2C9, and CYP3A4. As the transcriptional activity of PXR and CAR is not affected by IL-6 in cell-based reporter assays, our data suggest that the loss of CYP2 and CYP3 inducibility results from the negative regulation of PXR and CAR gene expression by this cytokine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Cytochrome P-450 Enzyme System / metabolism
  • Down-Regulation
  • Humans
  • Interleukin-6 / metabolism
  • Interleukin-6 / pharmacology*
  • Liver / metabolism*
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Steroid / metabolism*
  • Signal Transduction / drug effects*
  • Trans-Activators / metabolism*
  • Transcription Factors*

Substances

  • Interleukin-6
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Trans-Activators
  • Transcription Factors
  • constitutive androstane receptor
  • Cytochrome P-450 Enzyme System