Progesterone metabolites as farnesoid X receptor inhibitors.

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Abu-Hayyeh S, Williamson C

Progesterone metabolites as farnesoid X receptor inhibitors.

Dig Dis. 2015;33(3):300-6. doi: 10.1159/000371565. Epub 2015 May 27.

PubMed ID

26045261 [ View in PubMed

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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 micromol/L in an uncomplicated pregnancy and rise to approximately 40 micromol/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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Progesterone	Bile salt export pump	Protein	Humans	Unknown	Inhibitor	Details
Progesterone	Sodium/bile acid cotransporter	Protein	Humans	Unknown	Inhibitor	Details