Inhibition of Na+-taurocholate Co-transporting polypeptide-mediated bile acid transport by cholestatic sulfated progesterone metabolites.
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 [(3)H]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 [(3)H]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.
Abu-Hayyeh
Shadi
S
Institute for Reproductive and Developmental Biology, Imperial College London, London W12 0NN, United Kingdom.
Martinez-Becerra
Pablo
P
Sheikh Abdul Kadir
Siti H
SH
Selden
Clare
C
Romero
Marta R
MR
Rees
Myrddin
M
Marschall
Hanns-Ulrich
HU
Marin
Jose J G
JJ
Williamson
Catherine
C
D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002779:Cholestasis; D003035:Cobalt / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009865:Oocytes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011247:Pregnancy; D011374:Progesterone / Q000737:chemistry*; D012964:Sodium / Q000737:chemistry / Q000494:pharmacology*; D013256:Steroids / Q000378:metabolism; D013656:Taurocholic Acid / Q000737:chemistry*; D014982:Xenopus laevis
D001647:Bile Acids and Salts; D010455:Peptides; D013256:Steroids; D003035:Cobalt; D011374:Progesterone; D013656:Taurocholic Acid; D012964:Sodium