Hudon-Thibeault, Andrée-Anne; Lopez de los Santos, Yossef; Doucet, Nicolas 
ORCID: https://orcid.org/0000-0002-1952-9380; Sanderson, J. Thomas ORCID: https://orcid.org/0000-0002-3190-2811 et Vaillancourt, Cathy ORCID: https://orcid.org/0000-0003-0543-6244
(2018).
Serotonin reuptake inhibitors alter placental aromatase activity in human primary villous trophoblasts
In: Meeting of the International-Federation-of-Placenta-Associations (IFPA), 21-24 September 2018, Tokyo, Japon.
Résumé
Objectives: Serotonin reuptake inhibitors (SRIs), the main antidepressants prescribed to pregnant women, were previously shown to alter fetoplacental steroidogenesis in an in vitro co-culture model. This study aims to determine if and how SRIs regulate estrogen production by placental aromatase in primary villous trophoblasts.
Methods: Affinities of SRIs (fluoxetine, norfluoxetine, paroxetine, citalopram, sertraline and venlafaxine) for the substrate binding pocket of CYP19 were assessed by molecular docking analyses in silico. Primary villous trophoblasts isolated from term placentas were treated with serotonin, 5-HT2A agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and SRIs. CYP19 activity was determined by tritiated-water-release assay. Phosphorylation of CYP19 was determined by immunoprecipitation using SureBeads, followed by western blot using anti-phosphotyrosine (Y), threonine (T) or serine (S). Putative CYP19 phosphorylation sites were assessed using the Vienna-PTM web server, modeled using the energy mimized, crystallized form of CYP19 (PDB 5JL6) .
Results: All SRIs had a binding affinity for the substrate binding pocket of CYP19, suggesting the potential for competitive inhibition. Aromatase activity was decreased in the presence of fluoxetine (by 13.3% at 0.3 mM), sertraline (by 33.2% at 0.03 mM), paroxetine (by 33.6% at 0.03 mM and 40.6% at 0.1 mM) and venlafaxine (by 30.7% at 1 mM), whereas it was increased by serotonin (130% at 3 mM and 136% at 10 mM) and by DOI (192% at 10 mM and 206% at 30 mM) DOI was associated with an increase in phosphorylation of tyrosine (2.5- and 1.5-fold after 1h and 24h, respectively) and serine (3.4- fold after 24h). Our modeling results show that putative phosphorylation at residues Y361, Y441 and S363 may impact heme stabilization, whereas phosphorylation at residues S118 or S478 may alter substrate binding.
Conclusion: Our results contribute to a better understanding of the interactions of 5-HT and SRIs with CYP19 and suggest that SRI treatment during pregnancy disrupt placental estrogen production.
| Type de document: | Document issu d'une conférence ou d'un atelier |
|---|---|
| Informations complémentaires: | Affiche scientifique P2.47 Placenta (2019)83:E35 |
| Mots-clés libres: | - |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 15 juill. 2021 14:41 |
| Dernière modification: | 16 févr. 2022 15:25 |
| URI: | https://espace.inrs.ca/id/eprint/11726 |
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