title: Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3.
abstract: Bile acids, the metabolites of cholesterol, are signaling molecules that play critical role in many physiological functions. They undergo enterohepatic circulation through various transporters expressed in intestine and liver. Human organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of bile acids such as taurocholic acid. However, the transport properties of individual bile acids are not well understood. Therefore, we selected HEK293 cells overexpressing OATP1B1 and OATP1B3 to evaluate the transport of five major human bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, lithocholic acid) together withtheir glycine and taurine conjugates via OATP1B1 and OATP1B3. The bile acids were quantified by liquid chromatography-tandem mass spectrometry. The present study revealed that cholic acid, chenodeoxyxcholic acid, and deoxycholic acid were transported by OATP1B1 and OATP1B3, while ursodeoxycholic acid and lithocholic acid were not significantly transported by OATPs. However, all the conjugated bile acids were taken up rapidly by OATP1B1 and OATP1B3. Kinetic analyses revealed the involvement of saturable OATP1B1- and OATP1B3-mediated transport of bile acids. The apparent Km values for OATP1B1 and OATP1B3 of the conjugated bile acids were similar (0.74-14.7 μM for OATP1B1 and 0.47-15.3 μM for OATP1B3). They exhibited higher affinity than cholic acid (47.1 μM for OATP1B1 and 42.2 μM for OATP1B3). Our results suggest that conjugated bile acids (glycine and taurine) are preferred to unconjugated bile acids as substrates for OATP1B1 and OATP1B3.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suga
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.|Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Hiroaki
authors.identifier: http://orcid.org/0000-0003-3021-6120
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Maekawa
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Goto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.|Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport; D005998:Glycine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism*; D015394:Molecular Structure; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D001647:Bile Acids and Salts; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D005998:Glycine