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Induction of intestinal multidrug resistance-associated protein 2 (Mrp2) by spironolactone in rats

María L Ruiz1, Silvina S M Villanueva, Marcelo G Luquita

  • 1Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (Universidad Nacional de Rosario), Suipacha 570, (2000) Rosario, Argentina.

European Journal of Pharmacology
|September 22, 2009
PubMed

Insights

Spironolactone (SL) pretreatment increases intestinal multidrug resistance-associated protein 2 (Mrp2) in rats. This effect is mediated transcriptionally via the pregnane X receptor (PXR), suggesting therapeutic potential.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Gastroenterology

Background:

  • Intestinal drug transport is crucial for drug efficacy and toxicity.
  • Multidrug resistance-associated protein 2 (Mrp2) plays a key role in intestinal efflux transport.
  • Understanding modulators of Mrp2 expression is important for drug development.

Purpose of the Study:

  • To investigate the effect of spironolactone (SL) on intestinal Mrp2 expression and activity in rats.
  • To elucidate the regulatory mechanism underlying SL-induced changes in Mrp2.
  • To explore the potential therapeutic applications of SL related to Mrp2 function.

Main Methods:

  • Spironolactone pretreatment in rats.
  • Western blotting to assess Mrp2 protein levels.
  • Real-time PCR for Mrp2 mRNA quantification.
  • Ketoconazole administration to block PXR.
  • Jejunal sac model for transport studies.

Main Results:

  • Spironolactone significantly increased Mrp2 protein levels in the upper small intestine.
  • Mrp2 mRNA levels were elevated, suggesting transcriptional regulation.
  • Ketoconazole administration prevented the SL-induced increase in Mrp2 mRNA.
  • SL enhanced the transport activity of Mrp2.

Conclusions:

  • Spironolactone induces intestinal Mrp2 expression transcriptionally.
  • The pregnane X receptor (PXR) is a potential mediator of this induction.
  • Spironolactone may have therapeutic applications in conditions with reduced intestinal Mrp2 activity.

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