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Drug Metabolism and Disposition Fast Forward
First published on March 22, 2006; DOI: 10.1124/dmd.106.009316

0090-9556/06/3406-1030-1034$20.00
DMD 34:1030-1034, 2006

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ETHYNYLESTRADIOL INCREASES EXPRESSION AND ACTIVITY OF RAT LIVER MRP3

María L. Ruiz, Silvina S. M. Villanueva, Marcelo G. Luquita, Mary Vore, 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 Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky (M.V.)

We evaluated the effect of ethynylestradiol (EE) administration (5 mg/kg b.wt. s.c., for 5 consecutive days) on the expression and activity of multidrug resistance-associated protein 3 (Mrp3) in rats. Western blotting analysis revealed decreased Mrp2 (-41%) and increased Mrp3 (+200%) expression by EE. To determine the functional impact of up-regulation of Mrp3 versus Mrp2, we measured the excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, into bile and perfusate in the recirculating isolated perfused liver (IPL) model. APAP-glu was generated endogenously from acetaminophen (APAP), which was administered as a tracer dose (2 µmol/ml) into the perfusate. Biliary excretion of APAP-glu after 60 min of perfusion was reduced in EE-treated rats (-80%). In contrast, excretion into the perfusate was increased by EE (+45%). Liver content of APAP-glu at the end of the experiment was reduced by 36% in the EE group. The total amount of glucuronide remained the same in both groups. Taken together, these results indicate that up-regulation of Mrp3 led to an exacerbated basolateral versus canalicular excretion of conjugated APAP in IPL. We conclude that induced expression of basolateral Mrp3 by EE may represent a compensatory mechanism to prevent intracellular accumulation of common Mrp substrates, either endogenous or exogenous, due to reduced expression and activity of apical Mrp2.

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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