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

The effect of spironolactone (SL) pretreatment (200 μmol/kg b.w./day, 3 consecutive days) on intestinal multidrug resistance-associated protein 2 (Mrp2) was evaluated in rats. A significant increase in protein levels in upper regions of small intestine, where Mrp2 is mainly present, was detected by...

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Published in:European journal of pharmacology 2009-11, Vol.623 (1), p.103-106
Main Authors: Ruiz, María L., Villanueva, Silvina S.M., Luquita, Marcelo G., Pellegrino, José M., Rigalli, Juan P., Arias, Agostina, Sánchez Pozzi, Enrique J., Mottino, Aldo D., Catania, Viviana A.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biological Transport - drug effects
Cell Polarity
Dinitrochlorobenzene - metabolism
Dinitrochlorobenzene - pharmacokinetics
Gene Expression Regulation - drug effects
Glutathione - analogs & derivatives
Glutathione - analysis
Intestinal transport
Intestine, Small - drug effects
Intestine, Small - metabolism
Male
Medical sciences
Microvilli - metabolism
Microvilli - ultrastructure
Multidrug resistance-associated protein 2 (Mrp2)
Multidrug Resistance-Associated Proteins - genetics
Multidrug Resistance-Associated Proteins - metabolism
Organ Specificity
Pharmacology. Drug treatments
Polymerase Chain Reaction
Rats
Rats, Wistar
Receptors, Steroid - antagonists & inhibitors
RNA, Messenger - metabolism
Spironolactone
Spironolactone - pharmacology
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Summary:The effect of spironolactone (SL) pretreatment (200 μmol/kg b.w./day, 3 consecutive days) on intestinal multidrug resistance-associated protein 2 (Mrp2) was evaluated in rats. A significant increase in protein levels in upper regions of small intestine, where Mrp2 is mainly present, was detected by western blotting. Real time PCR studies suggest a transcriptional regulation. The administration of ketoconazole, a pregnane X receptor (PXR) antagonist, was able to prevent the increase in Mrp2 mRNA levels induced by SL. The serosal to mucosal transport of dinitrophenyl S-glutathione, a model substrate of Mrp2 was evaluated in jejunal sac model. The data indicate that SL increased Mrp2 activity, well correlating with its up-regulation. We conclude that SL is able to induce intestinal Mrp2 transcriptionally, PXR being a potential mediator. We propose that SL could be of potential therapeutic application particularly in situations of down-regulation of intestinal Mrp2.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2009.09.014