Comparison of “Type I” and “Type II” Organic Cation Transport by Organic Cation Transporters and Organic Anion-Transporting Polypeptides
- Jessica E. van Montfoort2,
- Michael Müller3,
- Geny M. M. Groothuis2,
- Dirk K. F. Meijer2,
- Hermann Koepsell4 and
- Peter J. Meier1
- 1Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zürich, Switzerland (J.E.v.M., P.J.M.); 2Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, Groningen, The Netherlands (J.E.v.M., G.M.M.G., D.K.F.M.); 3Sub-department of Human Nutrition and Epidemiology, Nutrition, Metabolism, and Genomics Group, Wageningen University and Research Center, Wageningen, The Netherlands (M.M.); and4Department of Anatomy, University of Würzburg, Würzburg, Germany (H.K.)
- Prof. Dr. Peter J. Meier-Abt, Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, CH-8091 Zürich, Switzerland. E-mail: meierabt{at}kpt.unizh.ch
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-injectedXenopus laevis oocytes. Based on characteristiccis-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 substrateN-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.
Footnotes
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This work was supported by the Swiss National Science Foundation (Grant 3100-045536.95 to P.J.M.). J.E.v.M. was supported by an Ubbo Emmius scholarship of the University of Groningen. A preliminary report of this study was presented at the 35th Annual Meeting of the European Association for the Study of the Liver (EASL) in Rotterdam, April 29–May 3, 2000, and published in abstract form [JHepatol32 (Suppl 2):118].
- Abbreviations:
- TEA
- tetraethylammonium
- TBuMA
- tributylmethylammonium
- PAEB
- procainamide ethobromide
- APM
- azidoprocainamide methoiodide
- rOCT1
- rat organic cation transporter 1
- Oatp2
- rat organic anion-transporting polypeptide 2
- APDA
- N-(4,4-azo-n-pentyl)-21-deoxyajmalinium
- hOCT1
- human organic cation transporter 1
- OATP-A
- human organic anion-transporting polypeptide A
- QD
- quinidine
- APQ
- N-(4,4-azo-n-pentyl)-quinuclidine
- NMQ
- N-methyl-quinine
- NMQD
- N-methyl-quinidine
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- Received January 16, 2001.
- Accepted March 16, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
