Cloning and Functional Expression of a Human Liver Organic Cation Transporter
- 1 June 1997
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 51 (6), 913-921
- https://doi.org/10.1124/mol.51.6.913
Abstract
Polyspecific organic cation transporters in the liver mediate the elimination of a wide array of endogenous amines and xenobiotics. In contrast to our understanding of the mechanisms of organic cation transport in rat liver, little is known about the mechanisms of organic cation transport in the human liver. We report the cloning, sequencing, and functional characterization of the first human polyspecific organic cation transporter from liver (hOCT1). hOCT1 (554 amino acids) is 78% identical to the previously cloned organic cation transporter from rat, rOCT1 [Nature (Lond.) 372:549–552 (1994)]. InXenopus laevis oocytes injected with the cRNA of hOCT1, the specific uptake of the organic cation3H-1-methyl-4-phenylpyridinium (3H-MPP+) was significantly enhanced (8-fold) over that in water-injected oocytes. Uptake of3H-MPP+ was saturable (Km = 14.6 ± 4.39 μm) and sensitive to membrane potential. Both small monovalent organic cations such as tetraethylammonium andN1-methylnicotinamide and bulkier organic cations (e.g., vecuronium and decynium-22) inhibited the uptake of3H-MPP+. In addition, the bile acid taurocholate inhibited the uptake of 3H-MPP+ in oocytes expressing hOCT1. Northern analysis demonstrated that the mRNA transcript of hOCT1 is expressed primarily in the human liver, whereas the mRNA transcript of rOCT1 is found in rat kidney, liver, intestine, and colon [Nature (Lond.) 372:549–552 (1994)]. In comparison to rOCT1, hOCT1 exhibits notable differences in its kinetic characteristics and tissue distribution. The functional expression of hOCT1 will provide a powerful tool for elucidation of the mechanisms of organic cation transport in the human liver and understanding of the mechanisms involved in the disposition and hepatotoxicity of drugs.Keywords
This publication has 29 references indexed in Scilit:
- Electrogenic Properties and Substrate Specificity of the Polyspecific Rat Cation Transporter rOCT1Published by Elsevier BV ,1996
- cDNA Cloning and Functional Expression of a Novel Rat Kidney Organic Cation Transporter, OCT2Biochemical and Biophysical Research Communications, 1996
- Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transportBiochimica et Biophysica Acta (BBA) - Reviews on Biomembranes, 1995
- Drug excretion mediated by a new prototype of polyspecific transporterNature, 1994
- Characterization of transport in isolated human hepatocytes: A study with the bile acid taurocholic acid, the uncharged ouabain and the organic cations vecuronium and rocuroniumBiochemical Pharmacology, 1994
- Membrane transport proteins: implications of sequence comparisonsCurrent Opinion in Cell Biology, 1992
- Membrane protein structure predictionJournal of Molecular Biology, 1992
- Carrier-mediated transport in the hepatic distribution and elimination of drugs, with special reference to the category of organic cationsJournal of Pharmacokinetics and Biopharmaceutics, 1990
- The scanning model for translation: an update.The Journal of cell biology, 1989
- A simple method for displaying the hydropathic character of a proteinJournal of Molecular Biology, 1982