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...
| Authors: | ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Published version |
| Publication date: | 2016 |
| Country: | España |
| Institution: | Universidad de Barcelona |
| Repository: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/105539 |
| Online Access: | https://hdl.handle.net/2445/105539 |
| Access Level: | Open access |
| Keyword: | Farmacogenètica Malalties infeccioses VIH (Virus) Terapèutica Pharmacogenetics Communicable diseases HIV (Viruses) Therapeutics |
| _version_ | 1878739505636179968 |
|---|---|
| author | Arimany Nardi, Cristina |
| author2 | Minuesa, Gerard Keller, Thorsten Erkizia, Itziar Koepsell, Hermann Martínez Picado, Francisco Javier Pastor Anglada, Marçal |
| author2_role | author author author author author author |
| author_browse | Arimany Nardi, Cristina Erkizia, Itziar Keller, Thorsten Koepsell, Hermann Martínez Picado, Francisco Javier Minuesa, Gerard Pastor Anglada, Marçal |
| author_facet | Arimany Nardi, Cristina Minuesa, Gerard Keller, Thorsten Erkizia, Itziar Koepsell, Hermann Martínez Picado, Francisco Javier Pastor Anglada, Marçal |
| author_role | author |
| collection | Dipòsit Digital de la UB |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_c2c0eada0d130a4eb9c2c1904b79615e |
| institution | Universidad de Barcelona |
| instname_str | Universidad de Barcelona |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:diposit.ub.edu:2445/105539 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | Frontiers Media |
| publisherStr | Frontiers Media |
| reponame_str | Dipòsit Digital de la UB |
| spelling | Role of human Organic Cation Transporter 1 (hOCT1) polymorphisms in lamivudine (3TC) uptake and drug-drug interactions. Arimany Nardi, Cristina Minuesa, Gerard Keller, Thorsten Erkizia, Itziar Koepsell, Hermann Martínez Picado, Francisco Javier Pastor Anglada, Marçal Farmacogenètica Malalties infeccioses VIH (Virus) Terapèutica Pharmacogenetics Communicable diseases HIV (Viruses) Therapeutics 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. Frontiers Media https://hdl.handle.net/2445/105539 |
| 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 |
| status_str | publishedVersion |
| title | 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_short | 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. |
| topic | Farmacogenètica Malalties infeccioses VIH (Virus) Terapèutica Pharmacogenetics Communicable diseases HIV (Viruses) Therapeutics |
| topic_facet | Farmacogenètica Malalties infeccioses VIH (Virus) Terapèutica Pharmacogenetics Communicable diseases HIV (Viruses) Therapeutics |
| url | https://hdl.handle.net/2445/105539 |