title: Induction of intestinal multidrug resistance-associated protein 2 (Mrp2) by spironolactone in rats.
abstract: The effect of spironolactone (SL) pretreatment (200micromol/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.
authors.affiliation: Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (Universidad Nacional de Rosario), Suipacha 570, (2000) Rosario, Argentina.
authors.forename: María L
authors.initials: ML
authors.lastname: Ruiz
authors.forename: Silvina S M
authors.initials: SS
authors.lastname: Villanueva
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Luquita
authors.forename: José M
authors.initials: JM
authors.lastname: Pellegrino
authors.forename: Juan P
authors.initials: JP
authors.lastname: Rigalli
authors.forename: Agostina
authors.initials: A
authors.lastname: Arias
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Sánchez Pozzi
authors.forename: Aldo D
authors.initials: AD
authors.lastname: Mottino
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Catania
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016764:Cell Polarity; D004137:Dinitrochlorobenzene / Q000378:metabolism / Q000493:pharmacokinetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000031:analogs & derivatives / Q000032:analysis; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000378:metabolism / Q000648:ultrastructure; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors; D013148:Spironolactone / Q000494:pharmacology*
chemical_list: D004137:Dinitrochlorobenzene; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D013148:Spironolactone; C030190:S-(2,4-dinitrophenyl)glutathione