Abstract
The intestinal-derived secondary bile acid (BA) lithocholic acid (LCA) is hepatotoxic and is implicated in the pathogenesis of cholestatic diseases. LCA is an endogenous ligand of the xenobiotic nuclear receptor pregnane X receptor (PXR), but there is currently no consensus on the respective roles of hepatic and intestinal PXR in mediating protection against LCA in vivo. Under the conditions reported here, we show that mice lacking Pxr are resistant to LCA-mediated hepatotoxicity. This unexpected phenotype is found in association with enhanced urinary BA excretion and elevated basal expression of drug metabolism enzymes and the hepatic sulfate donor synthesis enzyme Papss2 in Pxr(−/−) mice. By subsequently comparing molecular responses to dietary and intraperitoneal administration of LCA, we made two other significant observations: 1) LCA feeding induces intestinal, but not hepatic, drug-metabolizing enzymes in a largely Pxr-independent manner; and 2) in contrast to LCA feeding, bypassing first-pass gut transit by intraperitoneal administration of LCA did induce hepatic detoxification machinery and in a Pxr-dependent manner. These data reconcile important discrepancies in the reported molecular responses to this BA and suggest that Pxr plays only a limited role in mediating responses to gut-derived LCA. Furthermore, the route of administration must be considered in the future planning and interpretation of experiments designed to assess hepatic responses to BAs, orally administered pharmaceuticals, and dietary toxins.
Footnotes
This work was supported in part by the Biotechnology and Biological Sciences Research Council; the Institute of Obstetric and Gynaecology Trust; the Biomedical Research Centre at Imperial College Healthcare NHS Trust; and GlaxoSmithKline.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029306
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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- BA
- bile acid
- LCA
- lithocholic acid
- PXR
- pregnane X receptor
- CAR
- constitutive androstane receptor
- VDR
- vitamin D receptor
- P450
- cytochrome P450
- ALT
- alanine aminotransferase
- PCR
- polymerase chain reaction.
- Received July 1, 2009.
- Accepted September 30, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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