Abstract
ABCG2 is involved in epithelial transport/barrier functions. Here, we have investigated its ability to transport bile acids in liver and placenta. Cholylglycylamido fluorescein (CGamF) was exported by WIF-B9/R cells, which do not express the bile salt export pump (BSEP). Sensitivity to typical inhibitors suggested that CGamF export was mainly mediated by ABCG2. In Chinese hamster ovary (CHO cells), coexpression of rat Oatp1a1 and human ABCG2 enhanced the uptake and efflux, respectively, of CGamF, cholic acid (CA), glycoCA (GCA), tauroCA, and taurolithocholic acid-3-sulfate. The ability of ABCG2 to export these bile acids was confirmed by microinjecting them together with inulin in Xenopus laevis oocytes expressing this pump. ABCG2-mediated bile acid transport was inhibited by estradiol 17β-d-glucuronide and fumitremorgin C. Placental barrier for bile acids accounted for <2-fold increase in fetal cholanemia despite >14-fold increased maternal cholanemia induced by obstructive cholestasis in pregnant rats. In rat placenta, the expression of Abcg2, which was much higher than that of Bsep, was not affected by short-term cholestasis. In pregnant rats, fumitremorgin C did not affect uptake/secretion of GCA by the liver but inhibited its fetal-maternal transfer. Compared with wild-type mice, obstructive cholestasis in pregnant Abcg2(−/−) knockout mice induced similar bile acid accumulation in maternal serum but higher accumulation in placenta, fetal serum, and liver. In conclusion, ABCG2 is able to transport bile acids. The importance of this function depends on the relative expression in the same epithelium of other bile acid exporters. Thus, ABCG2 may play a key role in bile acid transport in placenta, as BSEP does in liver.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This study was supported in part by the Instituto de Salud Carlos III, Spain [FIS CP05/0135, PI070517, PI080151]; Junta de Castilla y Leon, Spain [GR75–2008, SA023A11-2, SA070A11-2, BIO39/SA27/10, SANIDAD2011]; The Ministerio de Ciencia e Innovacion, Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica and the European Regional Development Fund, Spain [SAF2009-08493, SAF2010-15517]; and Fundacion Investigacion Medica, Mutua Madrileña, Spain [Convocatoria VI, 2009]. The group is member of the Network for Cooperative Research on Membrane Transport Proteins (REIT), cofunded by the Ministerio de Ciencia e Innovacion, Spain, and the European Regional Development Fund [BFU2007-30688-E/BFI]; and belongs to the Centro de Investigacion Biomedica en Red for Hepatology and Gastroenterology Research (CIBERehd), Instituto de Salud Carlos III, Spain.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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ABBREVIATIONS:
- ABC
- ATP-binding cassette
- BSEP
- bile salt export pump
- MDR
- multidrug-resistance protein
- MRP
- multidrug resistance-associated protein
- E217βG
- estradiol 17β-d-glucuronide
- FTC
- fumitremorgin C
- CA
- cholic acid
- GCA
- glycocholic acid
- TCA
- taurocholic acid
- TLCA
- taurolithocholic acid
- CGamF
- cholylglycylamido fluorescein
- TLCS
- taurolithocholic acid-3-sulfate
- wt
- wild-type
- PCR
- polymerase chain reaction
- CHO
- Chinese hamster ovary
- Oatp1a1
- organic anion-transporting polypeptide 1a1
- Uo
- uptake medium for transport studies with X. laevis oocytes
- Uc
- uptake medium for transport studies with mammalian cells
- MS/MS
- tandem mass spectrometry
- HPLC
- high-performance liquid chromatography.
- Received August 4, 2011.
- Accepted November 10, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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