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

Óscar BrizResearch Unit, University Hospital, Salamanca, SpainMarta R. RomeroLaboratory of Experimental Hepatology and Drug Targeting (HEVEFARM) University of Salamanca, andP. Martinez-BecerraLaboratory of Experimental Hepatology and Drug Targeting (HEVEFARM) University of Salamanca, andRocı́o I.R. Macı́asLaboratory of Experimental Hepatology and Drug Targeting (HEVEFARM) University of Salamanca, andMaría J. PerezResearch Unit, University Hospital, Salamanca and theFelipe Piñol JiménezGastroenterology Division, University Hospital, 37007 Salamanca, SpainFrancisco Gonzalez-San MartinGastroenterology Division, University Hospital, 37007 Salamanca, SpainJosé J.G. Marı́nLaboratory of Experimental Hepatology and Drug Targeting (HEVEFARM) University of Salamanca, and

2006en

ABI

Annotatsiya

In cholestasis, the accumulation of organic anions in hepatocytes is reduced by transporters (multidrug resistance-associated proteins and OSTalpha-OSTbeta) 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 17beta-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 approximately 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.

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DOI: 10.1074/jbc.m602048200

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