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Ivermectin induces P-glycoprotein expression and function through mRNA stabilization in murine hepatocyte cell line

Cécile Ménez1, Laïla Mselli-Lakhal, Magali Foucaud-Vignault

  • 1INRA UMR1331, Université de Toulouse, INP, TOXALIM, Toulouse, F-31027, France. cecile.menez@toulouse.inra.fr

Biochemical Pharmacology
|October 26, 2011
PubMed

Insights

Ivermectin increases the expression of P-glycoprotein (P-gp/MDR1) in liver cells by stabilizing its mRNA. This functional P-gp overexpression may explain reduced drug efficacy and parasite resistance to ivermectin.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Metabolism

Background:

  • Ivermectin is a crucial antiparasitic drug used in human and veterinary medicine.
  • Ivermectin is known to interact with P-glycoprotein (P-gp/MDR1), a key drug transporter.
  • The effect of ivermectin on P-gp expression levels was previously uninvestigated.

Purpose of the Study:

  • To investigate the influence of ivermectin on P-glycoprotein (P-gp/MDR1) expression in mouse hepatocytes.
  • To elucidate the molecular mechanisms underlying ivermectin-induced changes in P-gp expression.

Main Methods:

  • Primary mouse hepatocytes were exposed to ivermectin.
  • Messenger RNA (mRNA) levels of P-gp isoforms (Mdr1a, Mdr1b) were quantified using real-time RT-PCR.
  • Cellular efflux of the P-gp substrate calcein was measured.
  • Reporter cell lines were used to assess ligand activities of nuclear receptors.
  • Actinomycin D was employed to determine mRNA half-life.

Main Results:

  • Ivermectin caused a time- and concentration-dependent upregulation of Mdr1a and Mdr1b mRNA.
  • Ivermectin treatment enhanced the efflux of calcein, indicating functional P-gp.
  • The induction of Mdr1 mRNA by ivermectin was independent of CAR and PXR nuclear receptors.
  • Ivermectin prolonged the half-life of Mdr1a and Mdr1b mRNA, suggesting post-transcriptional regulation.

Conclusions:

  • Ivermectin induces P-glycoprotein (P-gp/MDR1) overexpression in hepatocytes.
  • This overexpression occurs via post-transcriptional stabilization of Mdr1 mRNA.
  • The findings provide insights into mechanisms of reduced ivermectin efficacy and parasite resistance.

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