High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy

PLoS One. 2013 May 24;8(5):e64101. doi: 10.1371/journal.pone.0064101. Print 2013.

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.

Aim: 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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics*
  • Adult
  • Case-Control Studies
  • Cholestasis, Intrahepatic / genetics*
  • Delivery, Obstetric
  • Female
  • Gene Expression Regulation / drug effects*
  • Humans
  • Neoplasm Proteins / genetics*
  • Placenta / drug effects*
  • Placenta / metabolism*
  • Pregnancy
  • Pregnancy Complications / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Trophoblasts / drug effects
  • Trophoblasts / metabolism
  • Ursodeoxycholic Acid / administration & dosage*

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Neoplasm Proteins
  • RNA, Messenger
  • Ursodeoxycholic Acid

Supplementary concepts

  • Intrahepatic Cholestasis of Pregnancy

Grant support

The study received funding from the University of Bologna (RFO). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.