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

0090-9556/07/3511-2060-2066$20.00
DMD 35:2060-2066, 2007

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Beneficial Effect of Spironolactone Administration on Ethynylestradiol-Induced Cholestasis in the Rat: Involvement of Up-Regulation of Multidrug Resistance-Associated Protein 2

María L. Ruiz, Silvina S.M. Villanueva, Marcelo G. Luquita, Shin-ichi Ikushiro, Aldo D. Mottino, and Viviana A. Catania

Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina (M.L.R., S.S.M.V., M.G.L., A.D.M., V.A.C.); and Toyama Prefectural University, Toyama, Japan (S.I.)

The effect of spironolactone (SL) administration on 17{alpha}-ethynylestradiol (EE)-induced cholestasis was studied, with emphasis on expression and activity of Mrps. Adult male Wistar rats were divided into 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 multidrug resistance-associated protein 2 (Mrp2) by 41% and increased that of Mrp3 by 200%, whereas SL only affected Mrp2 expression (+60%) with respect to controls. The EE+SL group showed increased levels of Mrp2 and Mrp3 to the same extent as that registered for the individual treatments. Real-time polymerase chain reaction studies indicated that up-regulation of Mrp2 and Mrp3 by SL and EE, respectively, was at the 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. Coadministration of rats with SL partially prevented (-53%) 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.

Address correspondence to: Dr. Viviana A. Catania, Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570 (2000) Rosario, Argentina. E-mail: vcatania{at}fbioyf.unr.edu.ar






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