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First published on March 22, 2006; DOI: 10.1124/dmd.106.009316

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Received for publication January 10, 2006.
Revised March 16, 2006.
Accepted for publication March 17, 2006.

Ethynylestradiol increases expression and activity of rat liver Mrp3

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

1 Instituto de Fisiologia Experimental (CONICET)- Fac. Cs Bioq. y Farm. (UNR). Argentina. 2 Graduate Center for Toxicology, University of Kentucky, USA.

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

Abstract

ABSTRACT We evaluated the effect of EE administration (5 mg/kg b.w., 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 vs 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 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 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 vs 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.


Key words: ABC transporters, drug induced liver disease, glucuronidation, hepatic transport, hepatobiliary transport, induction, MRP


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