ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites
The ATP-binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characteri...
| Autores: | , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/56481 |
| Acesso em linha: | http://hdl.handle.net/10230/56481 http://dx.doi.org/10.1111/jpi.12849 |
| Access Level: | acceso abierto |
| Palavra-chave: | ATP-binding cassette transporters Biological transport Lactation Melatonin Mice Tissue distribution |
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ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolitesÁlvarez-Fernández, LauraGómez-Gómez, ÀlexHaro, NoemíGarcía-Lino, Alba M.Álvarez, Ana I.Pozo Mendoza, Óscar J., 1975-Merino, GraciaATP-binding cassette transportersBiological transportLactationMelatoninMiceTissue distributionThe ATP-binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6-hydroxymelatonin, and 6-sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK-II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild-type and Abcg2-/- mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2-/- mice was between 1.5 and 6-fold higher compared to the wild-type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (>sixfold increase for 6-sulfatoxymelatonin in Abcg2-/- mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild-type compared with Abcg2-/- lactating female mice. In addition, melatonin metabolites showed a higher milk-to-plasma ratio in wild-type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity.The authors thank Dr. A. H. Schinkel (The Netherlands Cancer Institute, Amsterdam, The Netherlands) who provided parental MDCK-II cells and its murine Abcg2 and human ABCG2-transduced subclones, as well as Abcg2 knockout mice. We are grateful to Prof. James McCue for assistance with language editing. This work was supported by the research project RTI2018-100903-B-I00 and PID2021-125660OB-I00 (MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa”) and by predoctoral grants (FPU19/04169 grant to LAF) from the Spanish Ministry of Education, Culture and Sport.Wiley202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/56481http://dx.doi.org/10.1111/jpi.12849reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésJ Pineal Res. 2023 Mar;74(2):e12849info:eu-repo/grantAgreement/ES/2PE/RTI2018-100903-B-I00info:eu-repo/grantAgreement/ES/3PE/PID2021-125660OB-I00© 2023 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/564812026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites |
| title |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites |
| spellingShingle |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites Álvarez-Fernández, Laura ATP-binding cassette transporters Biological transport Lactation Melatonin Mice Tissue distribution |
| title_short |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites |
| title_full |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites |
| title_fullStr |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites |
| title_full_unstemmed |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites |
| title_sort |
ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites |
| dc.creator.none.fl_str_mv |
Álvarez-Fernández, Laura Gómez-Gómez, Àlex Haro, Noemí García-Lino, Alba M. Álvarez, Ana I. Pozo Mendoza, Óscar J., 1975- Merino, Gracia |
| author |
Álvarez-Fernández, Laura |
| author_facet |
Álvarez-Fernández, Laura Gómez-Gómez, Àlex Haro, Noemí García-Lino, Alba M. Álvarez, Ana I. Pozo Mendoza, Óscar J., 1975- Merino, Gracia |
| author_role |
author |
| author2 |
Gómez-Gómez, Àlex Haro, Noemí García-Lino, Alba M. Álvarez, Ana I. Pozo Mendoza, Óscar J., 1975- Merino, Gracia |
| author2_role |
author author author author author author |
| dc.subject.none.fl_str_mv |
ATP-binding cassette transporters Biological transport Lactation Melatonin Mice Tissue distribution |
| topic |
ATP-binding cassette transporters Biological transport Lactation Melatonin Mice Tissue distribution |
| description |
The ATP-binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6-hydroxymelatonin, and 6-sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK-II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild-type and Abcg2-/- mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2-/- mice was between 1.5 and 6-fold higher compared to the wild-type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (>sixfold increase for 6-sulfatoxymelatonin in Abcg2-/- mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild-type compared with Abcg2-/- lactating female mice. In addition, melatonin metabolites showed a higher milk-to-plasma ratio in wild-type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023 2023 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/56481 http://dx.doi.org/10.1111/jpi.12849 |
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http://hdl.handle.net/10230/56481 http://dx.doi.org/10.1111/jpi.12849 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
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J Pineal Res. 2023 Mar;74(2):e12849 info:eu-repo/grantAgreement/ES/2PE/RTI2018-100903-B-I00 info:eu-repo/grantAgreement/ES/3PE/PID2021-125660OB-I00 |
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http://creativecommons.org/licenses/by-nc/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc/4.0/ |
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openAccess |
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application/pdf application/pdf |
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Wiley |
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Wiley |
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