title: Progesterone metabolites as farnesoid X receptor inhibitors.
abstract: Sulfated progesterone metabolites rise 100-fold in the third trimester of human pregnancy and have been shown to be elevated further in the gestational disorder intrahepatic cholestasis of pregnancy (ICP). Typical concentrations of progesterone sulfates range from 1 to 10 µmol/L in an uncomplicated pregnancy and rise to approximately 40 µmol/L in ICP. At this level they can influence bile acid and lipid metabolism. Studies using human and rodent specimens have shown that sulfated metabolites of progesterone competitively inhibit bile acid homeostasis pathways by functioning as partial agonists of farnesoid X receptor (FXR). This explains the loss of induction of FXR target genes in ICP, and may explain susceptibility to hypercholanaemia and dyslipidaemia in the second half of human pregnancy. Furthermore, progesterone sulfates are competitive inhibitors of biliary influx (NTCP) and efflux (BSEP) transport proteins, actions likely to further exacerbate hypercholanaemia and cholestasis.
authors.affiliation: Women's Health Academic Centre, Kings College London, London, UK.
authors.forename: Shadi
authors.initials: S
authors.lastname: Abu-Hayyeh
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000209:etiology / Q000378:metabolism*; D002793:Cholic Acids / Q000097:blood*; D005260:Female; D006706:Homeostasis; D006801:Humans; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology / Q000378:metabolism*; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D027981:Symporters / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002793:Cholic Acids; D029363:Organic Anion Transporters, Sodium-Dependent; D011280:Pregnanolone; D011374:Progesterone; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C579439:epiallopregnanolone sulfate; C071908:sodium-bile acid cotransporter