Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.

Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymo...

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Autores: Arimany Nardi, Cristina, Minuesa, Gerard, Keller, Thorsten, Erkizia, Itziar, Koepsell, Hermann, Martínez Picado, Francisco Javier, Pastor Anglada, Marçal
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/105539
Acceso en línea:https://hdl.handle.net/2445/105539
Access Level:acceso abierto
Palabra clave:Farmacogenètica
Malalties infeccioses
VIH (Virus)
Terapèutica
Pharmacogenetics
Communicable diseases
HIV (Viruses)
Therapeutics
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spelling Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.Arimany Nardi, CristinaMinuesa, GerardKeller, ThorstenErkizia, ItziarKoepsell, HermannMartínez Picado, Francisco JavierPastor Anglada, MarçalFarmacogenèticaMalalties infecciosesVIH (Virus)TerapèuticaPharmacogeneticsCommunicable diseasesHIV (Viruses)TherapeuticsLamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.Frontiers Media2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/105539Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3389/fphar.2016.00175Frontiers in Pharmacology, 2016, vol. 7, p. 175https://doi.org/10.3389/fphar.2016.00175cc-by (c) Arimany Nardi, Cristina et al., 2016http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1055392026-05-27T06:46:51Z
dc.title.none.fl_str_mv Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
title Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
spellingShingle Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
Arimany Nardi, Cristina
Farmacogenètica
Malalties infeccioses
VIH (Virus)
Terapèutica
Pharmacogenetics
Communicable diseases
HIV (Viruses)
Therapeutics
title_short Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
title_full Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
title_fullStr Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
title_full_unstemmed Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
title_sort Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions.
dc.creator.none.fl_str_mv Arimany Nardi, Cristina
Minuesa, Gerard
Keller, Thorsten
Erkizia, Itziar
Koepsell, Hermann
Martínez Picado, Francisco Javier
Pastor Anglada, Marçal
author Arimany Nardi, Cristina
author_facet Arimany Nardi, Cristina
Minuesa, Gerard
Keller, Thorsten
Erkizia, Itziar
Koepsell, Hermann
Martínez Picado, Francisco Javier
Pastor Anglada, Marçal
author_role author
author2 Minuesa, Gerard
Keller, Thorsten
Erkizia, Itziar
Koepsell, Hermann
Martínez Picado, Francisco Javier
Pastor Anglada, Marçal
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Farmacogenètica
Malalties infeccioses
VIH (Virus)
Terapèutica
Pharmacogenetics
Communicable diseases
HIV (Viruses)
Therapeutics
topic Farmacogenètica
Malalties infeccioses
VIH (Virus)
Terapèutica
Pharmacogenetics
Communicable diseases
HIV (Viruses)
Therapeutics
description Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/105539
url https://hdl.handle.net/2445/105539
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fphar.2016.00175
Frontiers in Pharmacology, 2016, vol. 7, p. 175
https://doi.org/10.3389/fphar.2016.00175
dc.rights.none.fl_str_mv cc-by (c) Arimany Nardi, Cristina et al., 2016
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Arimany Nardi, Cristina et al., 2016
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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