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J. Biol. Chem., Vol. 281, Issue 41, 30326-30335, October 13, 2006

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OATP8/1B3-mediated Cotransport of Bile Acids and Glutathione

AN EXPORT PATHWAY FOR ORGANIC ANIONS FROM HEPATOCYTES?^*

Oscar Briz, Marta R. Romero¹, Pablo Martinez-Becerra, Rocio I. R. Macias, Maria J. Perez, Felipe Jimenez^¶, Francisco G. San Martin^¶, and Jose J. G. Marin²

From the Research Unit, University Hospital, Salamanca and the Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM) University of Salamanca, and ^¶Gastroenterology Division, University Hospital, 37007 Salamanca, Spain

In cholestasis, the accumulation of organic anions in hepatocytes is reduced by transporters (multidrug resistance-associated proteins and OST-OST) able to extrude them across the basolateral membrane. Here we investigated whether organic anion-transporting polypeptides (OATPs) may contribute to this function. Xenopus laevis oocytes expressing human carboxylesterase-1 efficiently loaded cholic acid (CA) methyl ester, which was cleaved to CA and exported. Expression of OATP8/1B3 enhanced CA efflux, which was trans-activated by taurocholate but trans-inhibited by reduced (GSH) and oxidized (GSSG) glutathione. Moreover, taurocholate and estradiol 17-D-glucuronide, but not bicarbonate and glutamate, cis-inhibited OATP8/1B3-mediated bile acid transport, whereas glutathione cis-stimulated this process, which involved the transport of glutathione itself with a stoichiometry of 2:1 (GSH/bile acid). No cis-activation by glutathione of OATP-C/1B1 was found. Using real time quantitative reverse transcription-PCR, the absolute abundance of OATP-A/1A2, OATP-C/1B1, and OATP8/1B3 mRNA in human liver biopsies was measured. In healthy liver, expression levels of OATP-C/1B1 were 5-fold those of OATP8/1B3 and >100-fold those of OATP-A/1A2. This situation was not substantially modified in several cholestatic liver diseases studied here. In conclusion, although both OATP-C/1B1 and OATP8/1B3 are highly expressed, and able to transport bile acids, their mechanisms of action are different. OATP-C/1B1 may be involved in uptake processes, whereas OATP8/1B3 may mediate the extrusion of organic anions by symporting with glutathione as a normal route of exporting metabolites produced by hepatocytes or preventing their intracellular accumulation when their vectorial traffic toward the bile is impaired.

Received for publication, March 3, 2006 , and in revised form, July 28, 2006.

^* This work was supported in part by the Junta de Castilla y Leon Grants SA013/04 and SA059A05, Ministerio de Ciencia y Tecnologia, Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica Grant BFI2003-03208, Fundacion Investigacion Medica Mutua Madrileña Conv-III, 2006, Instituto de Salud Carlos III, FIS Grants CP03/00093 and PI051547. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of Research Fellowship Grant PB98/0259 from the Ministerio de Ciencia y Tecnologia, Spain, and a research fellowship from the Foundation "Miguel Casado San Jose," Salamanca, Spain.

² To whom correspondence should be addressed: Dept. of Physiology and Pharmacology, Campus Miguel de Unamuno, E.D. S-09, 37007-Salamanca, Spain. Tel.: 34-923-294674; Fax: 34-923-294669; E-mail: jjgmarin{at}usal.es.

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