Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells
- Autores
- Tocchetti, Guillermo Nicolás; Dominguez, Camila Juliana; Zecchinati, Felipe; Arana, Maite Rocío; Ruiz, Maria Laura; Villanueva, Silvina Stella Maris; Weiss, Johanna; Mottino, Aldo Domingo; Rigalli, Juan Pablo
- Año de publicación
- 2018
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo, decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp.
Fil: Tocchetti, Guillermo Nicolás. University of Heidelberg; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Dominguez, Camila Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Zecchinati, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Arana, Maite Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Ruiz, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Weiss, Johanna. University of Heidelberg; Alemania
Fil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Rigalli, Juan Pablo. University of Heidelberg; Alemania. Radboud Universiteit Nijmegen; Países Bajos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina - Materia
-
ABC TRANSPORTERS
CAMP
DRUG-DRUG INTERACTIONS
MEMBRANE PROGESTERONE RECEPTOR
NOMEGESTROL ACETATE - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/87330
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oai:ri.conicet.gov.ar:11336/87330 |
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Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cellsTocchetti, Guillermo NicolásDominguez, Camila JulianaZecchinati, FelipeArana, Maite RocíoRuiz, Maria LauraVillanueva, Silvina Stella MarisWeiss, JohannaMottino, Aldo DomingoRigalli, Juan PabloABC TRANSPORTERSCAMPDRUG-DRUG INTERACTIONSMEMBRANE PROGESTERONE RECEPTORNOMEGESTROL ACETATEhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo, decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp.Fil: Tocchetti, Guillermo Nicolás. University of Heidelberg; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Dominguez, Camila Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Zecchinati, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Arana, Maite Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Ruiz, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Weiss, Johanna. University of Heidelberg; AlemaniaFil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Rigalli, Juan Pablo. University of Heidelberg; Alemania. Radboud Universiteit Nijmegen; Países Bajos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaPergamon-Elsevier Science Ltd2018-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/87330Tocchetti, Guillermo Nicolás; Dominguez, Camila Juliana; Zecchinati, Felipe; Arana, Maite Rocío; Ruiz, Maria Laura; et al.; Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 154; 8-2018; 118-1260006-2952CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0006295218301667info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bcp.2018.04.023info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:42:07Zoai:ri.conicet.gov.ar:11336/87330instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:42:07.239CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells |
title |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells |
spellingShingle |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells Tocchetti, Guillermo Nicolás ABC TRANSPORTERS CAMP DRUG-DRUG INTERACTIONS MEMBRANE PROGESTERONE RECEPTOR NOMEGESTROL ACETATE |
title_short |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells |
title_full |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells |
title_fullStr |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells |
title_full_unstemmed |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells |
title_sort |
Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells |
dc.creator.none.fl_str_mv |
Tocchetti, Guillermo Nicolás Dominguez, Camila Juliana Zecchinati, Felipe Arana, Maite Rocío Ruiz, Maria Laura Villanueva, Silvina Stella Maris Weiss, Johanna Mottino, Aldo Domingo Rigalli, Juan Pablo |
author |
Tocchetti, Guillermo Nicolás |
author_facet |
Tocchetti, Guillermo Nicolás Dominguez, Camila Juliana Zecchinati, Felipe Arana, Maite Rocío Ruiz, Maria Laura Villanueva, Silvina Stella Maris Weiss, Johanna Mottino, Aldo Domingo Rigalli, Juan Pablo |
author_role |
author |
author2 |
Dominguez, Camila Juliana Zecchinati, Felipe Arana, Maite Rocío Ruiz, Maria Laura Villanueva, Silvina Stella Maris Weiss, Johanna Mottino, Aldo Domingo Rigalli, Juan Pablo |
author2_role |
author author author author author author author author |
dc.subject.none.fl_str_mv |
ABC TRANSPORTERS CAMP DRUG-DRUG INTERACTIONS MEMBRANE PROGESTERONE RECEPTOR NOMEGESTROL ACETATE |
topic |
ABC TRANSPORTERS CAMP DRUG-DRUG INTERACTIONS MEMBRANE PROGESTERONE RECEPTOR NOMEGESTROL ACETATE |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo, decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp. Fil: Tocchetti, Guillermo Nicolás. University of Heidelberg; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Dominguez, Camila Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Zecchinati, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Arana, Maite Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Ruiz, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Weiss, Johanna. University of Heidelberg; Alemania Fil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Rigalli, Juan Pablo. University of Heidelberg; Alemania. Radboud Universiteit Nijmegen; Países Bajos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina |
description |
ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo, decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-08 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/87330 Tocchetti, Guillermo Nicolás; Dominguez, Camila Juliana; Zecchinati, Felipe; Arana, Maite Rocío; Ruiz, Maria Laura; et al.; Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 154; 8-2018; 118-126 0006-2952 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/87330 |
identifier_str_mv |
Tocchetti, Guillermo Nicolás; Dominguez, Camila Juliana; Zecchinati, Felipe; Arana, Maite Rocío; Ruiz, Maria Laura; et al.; Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 154; 8-2018; 118-126 0006-2952 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0006295218301667 info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bcp.2018.04.023 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-nd/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Pergamon-Elsevier Science Ltd |
publisher.none.fl_str_mv |
Pergamon-Elsevier Science Ltd |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613327393652736 |
score |
13.070432 |