title: Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides.
abstract: Previous inhibition studies with taurocholate and cardiac glycosides suggested the presence of separate uptake systems for small "type I" (system1) and for bulky "type II" (system2) organic cations in rat hepatocytes. To identify the transport systems involved in type I and type II organic cation uptake, we compared the organic cation transport properties of the rat and human organic cation transporter 1 (rOCT1; hOCT1) and of the organic anion-transporting polypeptides 2 and A (rat Oatp2; human OATP-A) in cRNA-injected Xenopus laevis oocytes. Based on characteristic cis-inhibition patterns of rOCT1-mediated tributylmethylammonium and Oatp2-mediated rocuronium uptake, rOCT1 and Oatp2 could be identified as the organic cation uptake systems1 and 2, respectively, in rat liver. While hOCT1 exhibited similar transport properties as rOCT1, OATP-A- but not Oatp2-mediated rocuronium uptake was inhibited by the OATP-A substrate N-methyl-quinidine. The latter substrate was also transported by rOCT1 and hOCT1, demonstrating distinct organic cation transport activities for rOCT1 and Oatp2 and overlapping organic cation transport activities for hOCT1 and OATP-A. Finally, the data demonstrate that unmethylated quinidine is transported by rOCT1, hOCT1, and OATP-A at pH 6.0, but not at pH 7.5, indicating that quinidine requires a positive charge for carrier-mediated uptake into hepatocytes. In conclusion, the studies demonstrate that in rat liver the suggested organic cation uptake systems1 and 2 correspond to rOCT1 and Oatp2, respectively. However, the rat-based type I and II organic cation transporter classification cannot be extended without modification from rat to human.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, Groningen, The Netherlands.
authors.forename: J E
authors.initials: JE
authors.lastname: van Montfoort
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: G M
authors.initials: GM
authors.lastname: Groothuis
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
authors.forename: H
authors.initials: H
authors.lastname: Koepsell
authors.forename: P J
authors.initials: PJ
authors.lastname: Meier
mesh_terms: D000732:Androstanols / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins; D002301:Cardiac Glycosides / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D003473:Neuromuscular Nondepolarizing Agents / Q000378:metabolism*; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000644:Quaternary Ammonium Compounds / Q000378:metabolism*; D051381:Rats; D000077123:Rocuronium; D000074058:Solute Carrier Family 22 Member 5; D000070590:Solute Carrier Proteins; D027981:Symporters; D014981:Xenopus
chemical_list: D000732:Androstanols; D027321:Anion Transport Proteins; D002301:Cardiac Glycosides; D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D003473:Neuromuscular Nondepolarizing Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000644:Quaternary Ammonium Compounds; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; C000705567:Slc22a4 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D000070590:Solute Carrier Proteins; D027981:Symporters; C043902:tri-n-butylmethylammonium; D000077123:Rocuronium