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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Alanine Transaminase / blood
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Animals
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Aryl Hydrocarbon Hydroxylases / genetics
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Bile Acids and Salts / blood
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Bile Acids and Salts / metabolism
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Bile Acids and Salts / urine
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Body Weight / drug effects
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Chemical and Drug Induced Liver Injury / blood
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Chemical and Drug Induced Liver Injury / pathology
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Cytochrome P-450 CYP3A / genetics
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism
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Cytochrome P450 Family 2
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Enzyme Induction / drug effects
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Female
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Gene Expression / drug effects
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Inactivation, Metabolic / physiology*
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Injections, Intraperitoneal
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Intestinal Mucosa / metabolism*
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Intestines / drug effects
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Lithocholic Acid / administration & dosage
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Lithocholic Acid / pharmacokinetics*
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Lithocholic Acid / pharmacology
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Liver / drug effects
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Liver / metabolism*
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Liver / pathology
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Male
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Membrane Proteins / genetics
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Membrane Transport Proteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multienzyme Complexes / genetics
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Pregnane X Receptor
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Receptors, Steroid / metabolism*
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Steroid Hydroxylases / genetics
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Sulfate Adenylyltransferase / genetics
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Sulfotransferases / genetics
Substances
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Bile Acids and Salts
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Membrane Proteins
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Membrane Transport Proteins
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Multienzyme Complexes
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Pregnane X Receptor
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Receptors, Steroid
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Lithocholic Acid
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Cytochrome P-450 Enzyme System
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Steroid Hydroxylases
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Aryl Hydrocarbon Hydroxylases
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CYP3A protein, mouse
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Cyp2b10 protein, mouse
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Cyp2c55 protein, mouse
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Cyp3a11 protein, mouse
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Cytochrome P-450 CYP3A
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Cytochrome P450 Family 2
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Alanine Transaminase
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PAPS synthetase
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Sulfate Adenylyltransferase
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Sulfotransferases
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alcohol sulfotransferase