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

RUIZ ML; VILLANUEVA SSM; LUQUITA MG; IKUSHIRO SI; MOTTINO AD; CATANIA VA

Drug Metabolism and Disposition

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Año: 2007 p. 2060 - 2066

0090-9556

The effect of spironolactone (SL) administration on 17-ethy-nylestradiol (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 (200mol/kg daily for 3 days, i.p.), EESL (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 pro-tein 2 (Mrp2) by 41% and increased that of Mrp3 by 200%, whereas SL only affected Mrp2 expression (60%) with respect to controls. The EESL 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.