title: Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences.
abstract: 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 microm [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 microm [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.
authors.affiliation: Epidauros Biotechnology, Bernried, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kerb
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brinkmann
authors.forename: Natalia
authors.initials: N
authors.lastname: Chatskaia
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gorbunov
authors.forename: Valentin
authors.initials: V
authors.lastname: Gorboulev
authors.forename: Esther
authors.initials: E
authors.lastname: Mornhinweg
authors.forename: Andrea
authors.initials: A
authors.lastname: Keil
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014981:Xenopus
chemical_list: D017931:DNA Primers; D027702:Organic Cation Transporter 1; D011994:Recombinant Proteins