title: High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy.
abstract: BACKGROUND
  Ursodeoxycholic acid (UDCA) administration in intrahepatic cholestasis of pregnancy (ICP) induces bile acids (BA) efflux from the foetal compartment, but the molecular basis of this transplacental transport is only partially defined.
  
  
  OBJECTIVE
  To determine if placental breast cancer resistance protein (BCRP), able to transport BA, is regulated by UDCA in ICP.
  
  
  METHODS
  32 pregnant women with ICP (14 untreated, 34.9±5.17 years; 18 treated with UDCA--25 mg/Kg/day, 32.7±4.62 years,) and 12 healthy controls (33.4±3.32 years) agreed to participate in the study. Placentas were obtained at delivery and processed for membrane extraction. BCRP protein expression was evaluated by immunoblotting techniques and chemiluminescence quantified with a luminograph measuring emitted photons; mRNA expression with real time PCR. Statistical differences between groups were evaluated by ANOVA with Dunn's Multiple Comparison test.
  
  
  RESULTS
  BCRP was expressed only on the apical membrane of the syncytiotrophoblast. A significant difference was observed among the three groups both for mRNA (ANOVA, p = 0.0074) and protein (ANOVA, p<0.0001) expression. BCRP expression was similar in controls and in the untreated ICP group. UDCA induced a significant increase in placental BCRP mRNA and protein expression compared to controls (350.7±106.3 vs 100±18.68% of controls, p<0.05 and 397.8±56.02 vs 100±11.44% of controls, p<0.001, respectively) and untreated ICP (90.29±17.59% of controls, p<0.05 and 155.0±13.87%, p<0.01).
  
  
  CONCLUSIONS
  Our results confirm that BCRP is expressed only on the apical membrane of the syncytiotrophoblast and show that ICP treatment with high dose UDCA significantly upregulates placental BCRP expression favouring BA efflux from the foetal compartment.
authors.affiliation: Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Italy. francesco.azzaroli@unibo.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Azzaroli
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Raspanti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Simoni
authors.forename: Marco
authors.initials: M
authors.lastname: Montagnani
authors.forename: Andrea
authors.initials: A
authors.lastname: Lisotti
authors.forename: Paolo
authors.initials: P
authors.lastname: Cecinato
authors.forename: Rosario
authors.initials: R
authors.lastname: Arena
authors.forename: Giuliana
authors.initials: G
authors.lastname: Simonazzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Farina
authors.forename: Nicola
authors.initials: N
authors.lastname: Rizzo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mazzella
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D016022:Case-Control Studies; D002780:Cholestasis, Intrahepatic / Q000235:genetics*; D036861:Delivery, Obstetric; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014580:Ursodeoxycholic Acid