title: ABC drug transporter and nuclear receptor expression in human cytotrophoblasts: influence of spontaneous syncytialization and induction by glucocorticoids.
abstract: OBJECTIVE
  ABC transporters in the human placenta play a major role in protecting the fetus against potential toxic drugs. The glucocorticoid dexamethasone has been shown to induce ABCB1 expression in enterocytes and hepatocytes. However, in placental cells, little data exists either for dexamethasone, betamethasone or prednisone while these three glucocorticoids may be used during pregnancy. We investigated the modulation of placental ABC transporter and nuclear receptor expression by these drugs.
  
  
  METHODS
  Cytotrophoblasts were isolated from normal full-term placentas. We first assessed the influence of spontaneous syncytialization on transporter and nuclear receptor gene expression by taking samples of cytotrophoblasts after 24, 48 and 72 h of cell culture (n = 7 placentas). Incubations were then conducted with dexamethasone (50 nM-1 μM), betamethasone (20-400 nM) and prednisone (50 nM-1 μM) versus no drug for 24 h (n = 6). mRNA expression was determined by qRT-PCR.
  
  
  RESULTS
  Influence of syncytialization was observed only for ABCB1, ABCC2 and ABCC5 gene expression between t = 24 and 48 h (p < 0.05). Therefore, the following induction studies were conducted between t = 48 h and 72 h. Dexamethasone and betamethasone significantly induced ABCB1 gene expression by around 4-fold (p < 0.01 and 0.001, respectively). In parallel, 100 nM betamethasone decreased the glucocorticoid receptor gene expression by 22% (p < 0.01). Prednisone showed no effect on transporter or receptor expression.
  
  
  CONCLUSIONS
  These results suggest that dexamethasone or betamethasone administration may decrease the maternal-fetal transfer of an associated treatment being ABCB1 substrate, which may be either protective or deleterious for the fetus depending on the treatment's therapeutic aim.
authors.affiliation: EA 3620, Université Paris Descartes, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Manceau
authors.forename: C
authors.initials: C
authors.lastname: Giraud
authors.forename: X
authors.initials: X
authors.lastname: Declèves
authors.forename: J M
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: F
authors.initials: F
authors.lastname: Artiguebieille
authors.forename: F
authors.initials: F
authors.lastname: Goffinet
authors.forename: H
authors.initials: H
authors.lastname: Chappuy
authors.forename: C
authors.initials: C
authors.lastname: Vinot
authors.forename: J M
authors.initials: JM
authors.lastname: Tréluyer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D001623:Betamethasone / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015726:Giant Cells / Q000166:cytology / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009994:Osmolar Concentration; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011241:Prednisone / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001623:Betamethasone; D003907:Dexamethasone; D005938:Glucocorticoids; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011241:Prednisone; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C120809:ABCC5 protein, human; C497713:NR3C1 protein, human