| Inhibition of Na+-taurocholate Co-transporting polypeptide-mediated bile acid transport by cholestatic sulfated progesterone metabolites. | |
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MedLine Citation:
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PMID: 20177056 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Shadi Abu-Hayyeh; Pablo Martinez-Becerra; Siti H Sheikh Abdul Kadir; Clare Selden; Marta R Romero; Myrddin Rees; Hanns-Ulrich Marschall; Jose J G Marin; Catherine Williamson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-02-20 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-24 Completed Date: 2010-06-17 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 16504-12 Citation Subset: IM |
Affiliation:
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Institute for Reproductive and Developmental Biology, Imperial College London, London W12 0NN, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile Acids and Salts / chemistry, metabolism Binding, Competitive Cell Line, Tumor Cholestasis Cobalt / chemistry* Dose-Response Relationship, Drug Female Hepatocytes / metabolism Humans Models, Biological Oocytes / metabolism Peptides / chemistry Pregnancy Progesterone / chemistry* Sodium / chemistry, pharmacology* Steroids / metabolism Taurocholic Acid / chemistry* Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/Peptides; 0/Steroids; 57-83-0/Progesterone; 7440-23-5/Sodium; 7440-48-4/Cobalt; 81-24-3/Taurocholic Acid |
| Comments/Corrections | |
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