title: Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake.
abstract: Transport of a series of 3H-radiolabeled C23, C24, and C27 bile acid derivatives was compared and contrasted in HeLa cell lines stably transfected with rat Na+/taurocholate cotransporting polypeptide (ntcp) or organic anion transporting polypeptide 1 (oatp1) in which expression was under regulation of a zinc-inducible promoter. Similar uptake patterns were observed for both ntcp and oatp1, except that unconjugated hyodeoxycholate was a substrate of oatp1 but not ntcp. Conjugated bile acids were transported better than nonconjugated bile acids, and the configuration of the hydroxyl groups (alpha or beta) had little influence on uptake. Although cholic and 23 norcholic acids were transported by ntcp and oatp1, other unconjugated bile acids (chenodeoxycholic, ursodeoxycholic) were not. In contrast to ntcp, oatp1-mediated uptake of the trihydroxy bile acids taurocholate and glycocholate was four- to eightfold below that of the corresponding dihydroxy conjugates. Ntcp mediated high affinity, sodium-dependent transport of [35S]sulfobromophthalein with a Km similar to that of oatp1-mediated transport of [35S]sulfobromophthalein (Km = 3.7 vs. 3.3 muM, respectively). In addition, for both transporters, uptake of sulfobromophthalein and taurocholic acid showed mutual competitive inhibition. These results indicate that the substrate specificity of ntcp is considerably broader than previously suspected and caution the extrapolation of transport data obtained in vitro to physiological function in vivo.
authors.affiliation: Marion Bessin Liver Research Center, 625 Ullmann Bldg., Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Hata
authors.forename: Pijun
authors.initials: P
authors.lastname: Wang
authors.forename: Nicole
authors.initials: N
authors.lastname: Eftychiou
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Ananthanarayanan
authors.forename: Ashok
authors.initials: A
authors.lastname: Batta
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
authors.forename: Allan W
authors.initials: AW
authors.lastname: Wolkoff
mesh_terms: D000818:Animals; D000838:Anions / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013379:Substrate Specificity; D013448:Sulfobromophthalein / Q000378:metabolism; D027981:Symporters; D013656:Taurocholic Acid / Q000494:pharmacology; D014162:Transfection
chemical_list: D000838:Anions; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002756:Cholagogues and Choleretics; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; C421102:Slco1a1 protein, rat; D027981:Symporters; D013448:Sulfobromophthalein; C071908:sodium-bile acid cotransporter; D012710:Serum Albumin, Bovine; D013656:Taurocholic Acid