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Inhibition of Na+-Taurocholate Co-transporting Polypeptide-mediated Bile Acid Transport by Cholestatic Sulfated Progesterone Metabolites

Abu-Hayyeh, S; Martinez-Becerra, P; Kadir, SHSA; Selden, C; Romero, MR; Rees, M; ... Williamson, C; + view all (2010) Inhibition of Na+-Taurocholate Co-transporting Polypeptide-mediated Bile Acid Transport by Cholestatic Sulfated Progesterone Metabolites. J BIOL CHEM , 285 (22) 16504 - 16512. 10.1074/jbc.M109.072140. Gold open access

Abstract

Sulfated progesterone metabolite (P4-S) levels are raised in normal pregnancy and elevated further in intrahepatic cholestasis of pregnancy (ICP), a bile acid-liver disorder of pregnancy. ICP can be complicated by preterm labor and intrauterine death. The impact of P4-S on bile acid uptake was studied using two experimental models of hepatic uptake of bile acids, namely cultured primary human hepatocytes (PHH) and Na+-taurocholate co-transporting polypeptide (NTCP)-expressing Xenopus laevis oocytes. Two P4-S compounds, allopregnanolone-sulfate (PM4-S) and epiallopregnanolone-sulfate (PM5-S), reduced [H-3] taurocholate (TC) uptake in a dose-dependent manner in PHH, with both Na+-dependent and-independent bile acid uptake systems significantly inhibited. PM5-S-mediated inhibition of TC uptake could be reversed by increasing the TC concentration against a fixed PM5-S dose indicating competitive inhibition. Experiments using NTCP-expressing Xenopus oocytes confirmed that PM4-S/PM5-S are capable of competitively inhibiting NTCP-mediated uptake of [H-3]TC. Total serum PM4-S + PM5-S levels were measured in non-pregnant and third trimester pregnant women using liquid chromatography-electrospray tandem mass spectrometry and were increased in pregnant women, at levels capable of inhibiting TC uptake. In conclusion, pregnancy levels of P4-S can inhibit Na+-dependent and-independent influx of taurocholate in PHH and cause competitive inhibition of NTCP-mediated uptake of taurocholate in Xenopus oocytes.

Type:Article
Title:Inhibition of Na+-Taurocholate Co-transporting Polypeptide-mediated Bile Acid Transport by Cholestatic Sulfated Progesterone Metabolites
Open access status:An open access publication
DOI:10.1074/jbc.M109.072140
Keywords:SALT EXPORT PUMP, INTRAHEPATIC CHOLESTASIS, COTRANSPORTING POLYPEPTIDE, ABCB4 GENE, PREGNANCY, HEPATOCYTES, RAT, DEXAMETHASONE, POLYMORPHISM, VARIANTS

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