3 research outputs found
Intestinal Detoxification Limits the Activation of Hepatic Pregnane X Receptor by Lithocholic AcidS⃞
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