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|||0000-0001-9911-8428, Keller, Thorsten, Erkizia, Itziar|||0000-0003-1244-8972, Koepsell, Hermann, Martínez Picado, Francisco Javier|||0000-0002-4916-2129, Pastor-Anglada, Marçal|||0000-0003-3712-1773
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:185931
Acceso en línea:https://ddd.uab.cat/record/185931
https://dx.doi.org/urn:doi:10.3389/fphar.2016.00175
Access Level:acceso abierto
Palabra clave:HOCT1
Pharmacogenetics
Lamivudine
HIV infection
Therapy
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spelling Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug InteractionsArimany-Nardi, CristinaMinuesa, Gerard|||0000-0001-9911-8428Keller, ThorstenErkizia, Itziar|||0000-0003-1244-8972Koepsell, HermannMartínez Picado, Francisco Javier|||0000-0002-4916-2129Pastor-Anglada, Marçal|||0000-0003-3712-1773HOCT1PharmacogeneticsLamivudineHIV infectionTherapyLamivudine (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.Universitat Autònoma de Barcelona 22016-01-0120162016-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/185931https://dx.doi.org/urn:doi:10.3389/fphar.2016.00175reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-52067-RMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2013-49042-RMinisterio de Educación y Ciencia SAF2011-23660open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:1859312026-06-06T12:50:31Z
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
HOCT1
Pharmacogenetics
Lamivudine
HIV infection
Therapy
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|||0000-0001-9911-8428
Keller, Thorsten
Erkizia, Itziar|||0000-0003-1244-8972
Koepsell, Hermann
Martínez Picado, Francisco Javier|||0000-0002-4916-2129
Pastor-Anglada, Marçal|||0000-0003-3712-1773
author Arimany-Nardi, Cristina
author_facet Arimany-Nardi, Cristina
Minuesa, Gerard|||0000-0001-9911-8428
Keller, Thorsten
Erkizia, Itziar|||0000-0003-1244-8972
Koepsell, Hermann
Martínez Picado, Francisco Javier|||0000-0002-4916-2129
Pastor-Anglada, Marçal|||0000-0003-3712-1773
author_role author
author2 Minuesa, Gerard|||0000-0001-9911-8428
Keller, Thorsten
Erkizia, Itziar|||0000-0003-1244-8972
Koepsell, Hermann
Martínez Picado, Francisco Javier|||0000-0002-4916-2129
Pastor-Anglada, Marçal|||0000-0003-3712-1773
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv HOCT1
Pharmacogenetics
Lamivudine
HIV infection
Therapy
topic HOCT1
Pharmacogenetics
Lamivudine
HIV infection
Therapy
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 2
2016-01-01
2016
2016-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/185931
https://dx.doi.org/urn:doi:10.3389/fphar.2016.00175
url https://ddd.uab.cat/record/185931
https://dx.doi.org/urn:doi:10.3389/fphar.2016.00175
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-52067-R
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2013-49042-R
Ministerio de Educación y Ciencia SAF2011-23660
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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