| The role of lithocholic acid in the regulation of bile acid detoxication, synthesis, and transport proteins in rat and human intestine and liver slices. | |
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MedLine Citation:
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PMID: 20888898 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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The effects of the secondary bile acid, lithocholic acid (LCA), a VDR, FXR and PXR ligand, on the regulation of bile acid metabolism (CYP3A isozymes), synthesis (CYP7A1), and transporter proteins (MRP3, MRP2, BSEP, NTCP) as well as nuclear receptors (FXR, PXR, LXRα, HNF1α, HNF4α and SHP) were studied in rat and human precision-cut intestine and liver slices at the mRNA level. Changes due to 5 to 10 μM of LCA were compared to those of other prototype ligands for VDR, FXR, PXR and GR. LCA induced rCYP3A1 and rCYP3A9 in the rat jejunum, ileum and colon, rCYP3A2 only in the ileum, rCYP3A9 expression in the liver, and CYP3A4 in the human ileum but not in liver. LCA induced the expression of rMRP2 in the colon but not in the jejunum and ileum but did not affect rMRP3 expression along the length of the rat intestine. In human ileum slices, LCA induced hMRP3 and hMRP2 expression. In rat liver slices, LCA decreased rCYP7A1, rLXRα and rHNF4α expression, induced rSHP expression, but did not affect rBSEP or rNTCP expression; whereas in the human liver, a small but significant decrease was found for hHNF1α expression. These data suggests profound species differences in the effects of LCA on bile acid transport, synthesis and detoxification. An examination of the effects of prototype VDR, PXR, GR and FXR ligands showed that these pathways are all intact in precision cut slices and that LCA exerted VDR, PXR and FXR effects. The LCA-induced altered enzymes and transporter expressions in the intestine and liver would affect the disposition of drugs. |
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Authors:
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Ansar A Khan; Edwin C Y Chow; Robert J Porte; K Sandy Pang; Geny M M Groothuis |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-01 |
Journal Detail:
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Title: Toxicology in vitro : an international journal published in association with BIBRA Volume: 25 ISSN: 1879-3177 ISO Abbreviation: Toxicol In Vitro Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2010-12-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8712158 Medline TA: Toxicol In Vitro Country: England |
Other Details:
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Languages: eng Pagination: 80-90 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Pharmacy, University of Groningen, Groningen, The Netherlands. |
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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MOP89850//Canadian Institutes of Health Research |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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