Induction of intestinal multidrug resistance-associated protein 2 (Mrp2) by spironolactone in rats.
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.
Ruiz
María L
ML
Instituto de Fisiología Experimental (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas (Universidad Nacional de Rosario), Suipacha 570, (2000) Rosario, Argentina.
Villanueva
Silvina S M
SS
Luquita
Marcelo G
MG
Pellegrino
José M
JM
Rigalli
Juan P
JP
Arias
Agostina
A
Sánchez Pozzi
Enrique J
EJ
Mottino
Aldo D
AD
Catania
Viviana A
VA
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*
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