Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequencesKerb, Reinholda; Brinkmann, Ulricha; Chatskaia, Nataliab; Gorbunov, Dmitryb; Gorboulev, Valentinb; Mornhinweg, Esthera; Keil, Andreaa; Eichelbaum, Michelc; Koepsell, HermannbPharmacogenetics: November 2002 - Volume 12 - Issue 8 - p 591-595 Original Articles Buy Abstract Author InformationAuthors By systematic mutation screening of the polyspecific organic cation transporter hOCT1 (SLC22A1) in 57 Caucasians, 25 genetic variations were identified and further analysed for population frequency. Five mutations resulting in the amino acid changes Arg61Cys, Cys88Arg, Phe160Leu, Gly401Ser, and Met420del, with respective allele frequencies of 9.1, 0.6, 22, 3.2, and 16%, were functionally characterized upon expression in Xenopus oocytes. Phe160Leu and Met420del exhibited substrate affinities and selectivites identical to hOCT1 wild-type. In contrast, uptake of 0.1 μm [3H]1-methyl-4-phenylpyridinium ([3H]MPP) by Arg61Cys, Cys88Arg and Gly401Ser were reduced to 30, 1.4 and 0.9% compared to wild-type, respectively. Since transport of 1 μm [3H]serotonin by Cys88Arg and Gly401Ser was reduced to only 13 and 12% of wild-type, these mutants exhibit a changed substrate selectivity. The data show that the mutants Arg61Cys, Cys88Arg and Gly401Ser could affect the disposition of OCT1 substrates and as a consequence may alter the duration and intensity of effects of drugs and neurotransmitters which are substrates for hOCT1. aEpidauros Biotechnology, Bernried, Germany, bInstitute for Anatomy and Cell Biology Julius-Maximilians-University, Würzburg, Germany and cDr Margarete Fischer-Bosch-Institute for Clinical Pharmacology, Stuttgart, Germany Correspondence to Professor Dr Hermann Koepsell, Institute of Anatomy and Cell Biology Koellikerstr. 6, 97070 Würzburg, Germany Tel: +49 0931 312700; fax: +49 0931 312087; e-mail: Hermann@Koepsell.de Received 17 May 2002 Accepted 11 July 2002 © 2002 Lippincott Williams & Wilkins, Inc.