title: In vitro modulation of estrogen receptor activity by norfluoxetine.
abstract: OBJECTIVE
  Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed for pregnancy and postpartum depression. However, these compounds can cross the placenta and also pass into breast milk, thus reaching the fetus and infant during critical developmental stages, potentially causing adverse effects. Fluoxetine, a widely used SSRI, has been shown to affect (neuro)endocrine signaling in various organisms, including humans. This compound can also interact with estrogen receptors in vitro and cause an estrogen-dependent uterotrophic response in rodents. Consequently, the aim of the present study was to assess if the active metabolite of fluoxetine, namely norfluoxetine (NFLX), shares the same capacity for estrogen receptor interaction.
  
  
  METHODS
  The in vitro (anti)estrogenic activity of norfluoxetine was assessed using a firefly luciferase reporter construct in the T47D-Kbluc breast cancer cell line. These cells express nuclear estrogen receptors (ERs) that can activate the transcription of the luciferase reporter gene upon binding of ER agonists. Light emission was monitored in case of cells exposed to norfluoxetine or mixtures of norfluoxetine-estradiol. Cell viability was assessed using a resazurin-based assay.
  
  
  RESULTS
  During individual testing, NFLX was able to induce a significant increase in luciferase activity compared to control, but only at the highest concentration tested (10 μM). In binary mixtures with estradiol (30 pM constant concentration) a significant increase in luminescence was observed at low submicromolar norfluoxetine concentrations compared to estradiol alone.
  
  
  CONCLUSIONS
  Norfluoxetine can induce estrogenic effects in vitro and can potentiate the activity of estradiol. However, further studies are needed to clarify if these observed estrogenic effects may have detrimental consequences for human exposure.
authors.affiliation: Department of Toxicology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Diana
authors.initials: D
authors.lastname: Lupu
authors.affiliation: Department of Toxicology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Anca
authors.initials: A
authors.lastname: Pop
authors.affiliation: Department of Toxicology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Julien
authors.initials: J
authors.lastname: Cherfan
authors.affiliation: Department of Toxicology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Department of Toxicology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Felicia
authors.initials: F
authors.lastname: Loghin
keywords: estrogen receptors; in vitro; norfluoxetine