Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to
pregnant women that suffer from depression. Placental cells are exposed to SRIs via
maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis
in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the
estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted
by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells.
Based on molecular simulations, the present study illustrates that the SRIs fluoxetine,
norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding
affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition.
Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas,
we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine
and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine,
paroxetine and sertraline decrease aromatase activity in primary villous trophoblast.
The effects of the paroxetine and sertraline in primary villous trophoblasts were
observed at the lower doses tested. We also showed that 5-HT and the 5-HT 2A receptor
agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase
in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation
of CYP19 was also associated with DOI treatment. Our results contribute to better
understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production.
Moreover, this study suggests that alteration of placental 5-HT levels due to depression
and/or SRI treatment during pregnancy may be associated with disruption of placental
estrogen production.