title: Effect of oxygen on multidrug resistance in term human placenta.
abstract: BACKGROUND
  The placenta contains efflux transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), that limit the passage of xenobiotics, certain hormones and nutrients from the maternal to the fetal circulation. The expression of these transporters changes with gestational age, yet the mechanisms involved remain unknown. However, the changes in P-gp and BCRP transporter expression coincide with those of oxygen tension in the placenta, and oxygen tension has been shown to modulate P-gp and BCRP expression in other tissues. The objective of this study was to investigate the effects of oxygen tension on P-gp and BCRP expression in the term human placenta.
  
  
  METHODS
  Following equilibration in culture (96 h), term placental explants (n = 7) were cultured in 3% or 20% oxygen for 24 and 48 h. Culture medium was collected every 24 h to measure lactate dehydrogenase (LDH; explant viability) and human chorionic gonadotropin (hCG; syncytiotrophoblast function). P-gp (encoded by ABCB1) and BCRP (encoded by ABCG2) protein and mRNA, as well as VEGFA mRNA were measured using western blot and qRT-PCR. P-gp localization was determined using immunofluorescence.
  
  
  RESULTS
  Oxygen tension had a significant effect on P-gp expression, with ABCB1/P-gp mRNA and protein levels increased in the hypoxic condition (3% O2) after 48 h (p < 0.05). VEGFA mRNA was elevated by hypoxia at both 24 and 48 h (p < 0.05). In contrast, placental ABCG2/BCRP mRNA and protein expression were stable with changes in oxygen tension. We identified profound differences in the glycosylation of P-gp between cultured and non-cultured placental tissue, with cultured explants expressing deglycosylated P-gp.
  
  
  CONCLUSIONS
  These findings demonstrate that, at term, the expression of placental P-gp, is regulated by oxygen tension. This suggests that changes in oxygenation of the placenta in the third trimester may alter levels of placental P-gp, and in doing so alter fetal exposure to P-gp substrates, including xenobiotics and certain hormones.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Javam
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: M C
authors.initials: MC
authors.lastname: Audette
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Bloise
authors.affiliation: Dept Ob-Gyn, University of Ottawa, Ottawa, Canada; Dept Cellular & Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Gibb
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada; Department of Ob-Gyn, University of Toronto, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada; Fraser Mustard Institute for Human Development, University of Toronto, Toronto, Canada. Electronic address: stephen.matthews@utoronto.ca.
authors.forename: S G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D006063:Chorionic Gonadotropin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010100:Oxygen / Q000008:administration & dosage*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D014327:Trophoblasts / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D006063:Chorionic Gonadotropin; D009363:Neoplasm Proteins; D007770:L-Lactate Dehydrogenase; D010100:Oxygen
keywords: BCRP; Hypoxia; Multidrug resistance; P-glycoprotein; Third-trimester placenta