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Drug Metabolism and Disposition Fast Forward
First published on August 8, 2007; DOI: 10.1124/dmd.107.016519

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Received for publication May 8, 2007.
Revised August 6, 2007.
Accepted for publication August 6, 2007.

BENEFICIAL EFFECT OF SPIRONOLACTONE ADMINISTRATION ON ETHYNYLESTRADIOL-INDUCED CHOLESTASIS IN THE RAT. INVOLVEMENT OF UP-REGULATION OF Mrp2

Maria Laura Ruiz 1, Silvina Stella Maris Villanueva 1, Marcelo Gabriel Luquita 1, Shin Ichi Ikushiro 2, Aldo Domingo Mottino 1, Viviana Alicia Catania 1*

1 Instituto de Fisiologia Experimental (CONICET)- Fac. Cs Bioq. y Farm. (UNR). Argentina. 2 Toyama Prefectural University

* Address correspondence to: E-mail: vcatania{at}fbioyf.unr.edu.ar

Abstract

The effect of spironolactone (SL) administration on 17{alpha}-ethynylestradiol (EE)-induced cholestasis was studied, with emphasis in expression and activity of Mrps. Adult male Wistar rats were divided in the following groups: EE (5 mg/kg daily for 5 days, s.c.), SL (200 µmol/kg daily for 3 days, i.p.); EE+SL (same doses, SL administered the last 3 days of EE treatment) and controls. SL prevented the decrease in bile salt independent fraction of bile flow induced by EE, in association with normalization of biliary excretion of glutathione. Western blot studies indicate that EE decreased the expression of Mrp2 by 41% and increased that of Mrp3 by 200%, whereas SL only affected Mrp2 expression (+60%) with respect to controls. EE+SL group showed increased levels of Mrp2 and Mrp3 to the same extent as registered for the individual treatments. Real time PCR studies indicated that up-regulation of Mrp2 and Mrp3 by SL and EE, respectively, were at transcriptional level. To estimate Mrp2 and Mrp3 activities, apical and basolateral excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, was measured in the recirculating isolated perfused liver model. Biliary/perfusate excretion ratio was decreased in EE (-88%) and increased in SL (+36%) with respect to controls. Co-administration of rats with SL partially prevented (-53%) from impairment induced by EE in this ratio. In conclusion, SL administration to EE-induced cholestatic rats counteracted the decrease in bile flow and biliary excretion of glutathione and APAP-glu, a model Mrp substrate, findings associated with up-regulation of Mrp2 expression.


Key words: ABC transporters, biliary excretion, drug transport, glucuronidation, hepatobiliary transport, MRP, phase II drug metabolism, UDP glucuronyltransferases




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