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

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J M Pascussi1, S Gerbal-Chaloin, L Pichard-Garcia

  • 1INSERM U128, IFR24, 1919 Route de Mende, Montpellier, 34293, France.

Biochemical and Biophysical Research Communications
|August 5, 2000
PubMed

Insights

Inflammation reduces drug metabolism by decreasing cytochrome P450s (CYP). Interleukin-6 (IL-6) lowers pregnane X receptor (PXR) and constitutively activated receptor (CAR) expression, impairing CYP induction.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Hepatic drug metabolism is impaired during inflammation and infection.
  • This impairment is linked to cytokine-mediated downregulation of cytochrome P450s (CYP).
  • The precise mechanism of this CYP repression remains unknown.

Purpose of the Study:

  • To investigate the mechanism by which interleukin-6 (IL-6) represses hepatic drug metabolism.
  • To determine the effect of IL-6 on the expression of key drug-metabolizing enzymes and their regulatory receptors.

Main Methods:

  • Primary cultures of human hepatocytes were treated with IL-6.
  • Expression levels of PXR, CAR, dioxin receptor, and glucocorticoid receptor mRNAs were quantified.
  • CYP induction by rifampicin and phenobarbital was measured.
  • Transcriptional activity of PXR and CAR was assessed using cell-based reporter assays.

Main Results:

  • IL-6 significantly decreased the mRNA expression of PXR and CAR.
  • IL-6 did not affect the mRNA levels of the dioxin receptor or glucocorticoid receptor.
  • IL-6 reduced the induction of CYP2B6, CYP2C8, CYP2C9, and CYP3A4 by rifampicin and phenobarbital.
  • The transcriptional activity of PXR and CAR was not directly inhibited by IL-6.

Conclusions:

  • IL-6 negatively regulates the gene expression of PXR and CAR.
  • This downregulation of PXR and CAR by IL-6 leads to the loss of inducibility of key drug-metabolizing CYP enzymes.
  • The findings elucidate a mechanism for impaired drug metabolism during inflammatory conditions.

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