Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy

J Hepatol. 2006 Jun;44(6):1150-7. doi: 10.1016/j.jhep.2005.09.017. Epub 2005 Nov 7.


Background/aims: Progesterone metabolites such as 5alpha-pregnan-3alpha-ol-20-one (PM4) are elevated in serum of women with intrahepatic cholestasis of pregnancy (ICP).

Methods/results: When assayed in isolated perfused rat liver, PM4 did not induce cholestasis, whereas sulfated PM4 (PM4-S), which unlike PM4 is secreted into bile, reduced bile flow and bile acid (BA) output. Whether PM4-S inhibited the bile salt export pump (BSEP) was investigated. Radiolabeled methylesters (ME) of cholic acid and chenodeoxycholic acid were taken up by Xenopus laevis oocytes co-expressing rat BSEP and human carboxylesterase-1 (CES1), efficiently hydrolyzed to free BAs by CES1 and subsequently exported by BSEP. Rifampicin or cyclosporin A in the extracellular medium had no effect on BA efflux. In contrast, estradiol 17beta-D-glucuronide and several progesterone metabolites, including PM4-S, induced a marked non-competitive trans-inhibition of BSEP-mediated BA efflux (Ki=20-60 microM). Mitochondrial activity was markedly impaired in oocytes incubated with BA-MEs, but not with free BAs. Co-expression of CES1 and BSEP partly protected oocytes from this toxic effect. Trans-inhibition of BSEP abolished this protection.

Conclusions: Several estrogens and progesterone metabolites are able to induce trans-inhibition of BSEP and the subsequent toxicity induced by the accumulation of BAs, which may play a role in the etiopathogenesis of ICP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Bile Acids and Salts / metabolism*
  • Carboxylic Ester Hydrolases / genetics
  • Carboxylic Ester Hydrolases / metabolism
  • Cholestasis, Intrahepatic / physiopathology*
  • Cholic Acid / metabolism
  • Female
  • Humans
  • Male
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Pregnancy
  • Pregnancy Complications / physiopathology*
  • Progesterone / metabolism*
  • Rats
  • Rats, Wistar
  • Steroids / pharmacology*
  • Xenopus laevis


  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Abcb11 protein, rat
  • Bile Acids and Salts
  • Steroids
  • Progesterone
  • Carboxylic Ester Hydrolases
  • CES1 protein, human
  • Cholic Acid