title: Characterization of the role of ABCG2 as a bile acid transporter in liver and placenta.
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.
authors.affiliation: Laboratory of Experimental Hepatology and Drug Targeting, National Institute for the Study of Liver and Gastrointestinal Diseases, University of Salamanca, Salamanca, Spain.
authors.forename: Alba G
authors.initials: AG
authors.lastname: Blazquez
authors.forename: Oscar
authors.initials: O
authors.lastname: Briz
authors.forename: Marta R
authors.initials: MR
authors.lastname: Romero
authors.forename: Ruben
authors.initials: R
authors.lastname: Rosales
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Monte
authors.forename: Javier
authors.initials: J
authors.lastname: Vaquero
authors.forename: Rocio I R
authors.initials: RI
authors.lastname: Macias
authors.forename: Doris
authors.initials: D
authors.lastname: Cassio
authors.forename: Jose J G
authors.initials: JJ
authors.lastname: Marin
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002779:Cholestasis; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D014018:Tissue Distribution
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D029362:Organic Anion Transporters, Sodium-Independent; C421102:Slco1a1 protein, rat; C037643:bile acid binding proteins