The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

@article{Staudinger2001TheNR,
  title={The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity},
  author={Jeff L. Staudinger and Bryan Goodwin and Stacey A. Jones and Diane Hawkins-Brown and Kathleen I. MacKenzie and Anne M. Latour and Yaping Liu and Curtis D. Klaassen and Kathleen K. Brown and J Reinhard and Timothy M. Willson and Beverly H. Koller and Steven A. Kliewer},
  journal={Proceedings of the National Academy of Sciences of the United States of America},
  year={2001},
  volume={98},
  pages={3369 - 3374}
}
The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16α-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol… Expand
Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor.
TLDR
Interestingly, both the antibiotic rifampicin and the herbal antidepressant St. John's wort activate PXR and have anticholestatic properties, which suggests that more potent, selective P XR agonists may be useful in the treatment of biliary cholestasis or other diseases characterized by the accumulation of bile acids or other toxins in the liver. Expand
Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)
TLDR
It is proposed that PXR serves as a master regulator of the phase I and II responses to facilitate rapid and efficient detoxification and elimination of foreign chemicals. Expand
Intestinal Detoxification Limits the Activation of Hepatic Pregnane X Receptor by Lithocholic Acid
TLDR
It is shown that mice lacking Pxr are resistant to LCA-mediated hepatotoxicity and suggested that PxR plays only a limited role in mediating responses to gut-derived LCA, and 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. Expand
Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor.
TLDR
Data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo. Expand
Regulation of cyp3a gene transcription by the pregnane x receptor.
TLDR
The pregnane X receptor (PXR) is a promiscuous nuclear receptor that has evolved to protect the body from toxic chemicals and may prove useful in the treatment of diseases in which toxic metabolites accumulate, such as cholestatic liver disease. Expand
The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.
TLDR
Although PXR evolved to protect the body, its activation by a variety of prescription drugs represents the molecular basis for an important class of harmful drug-drug interactions, so assays that detect PxR activity will be useful in developing safer prescription drugs. Expand
Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice
TLDR
It is revealed that PXR plays both positive and negative roles in regulating bilirubin homeostasis, and this provides a novel mechanism that may govern receptor cross‐talk and the hierarchy of xenobiotic and endobiotic regulation. Expand
REGULATORY NETWORKS OF PXR, CAR AND LXR IN CHOLESTEROL AND BILE ACID METABOLISM
TLDR
The combined loss of PXR and CAR resulted in a significantly heightened sensitivity to bile acid toxicity in a sex-specific manner and it is proposed that LXRs have evolved to have dual function in maintaining cholesterol and bile Acid homeostasis. Expand
Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites.
  • J. Sonoda, L. Chong, +5 authors R. Evans
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2005
TLDR
It is proposed that the P XR signaling pathway protects the body from toxic dietary cholesterol metabolites, and, by extension, PXR ligands may ameliorate human diseases such as cholestatic liver diseases and the associating acute renal failure. Expand
The Constitutive Androstane Receptor and Pregnane X Receptor Function Coordinately to Prevent Bile Acid-induced Hepatotoxicity*
TLDR
A central role for CAR in LCA detoxification is defined and results show that CAR and PXR function coordinately to regulate both xenobiotic and bile acid metabolism. Expand
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TLDR
The cloning and characterization of PXR is reported, which is remarkably divergent between species, with the rabbit, rat, and human receptors sharing only approximately 80% amino acid identity in their ligand-binding domains. Expand
Humanized xenobiotic response in mice expressing nuclear receptor SXR
TLDR
It is shown that targeted disruption of the mouse PXR gene abolishes induction of CYP3A by prototypic inducers such as dexamethasone or pregnenolone-16α-carbonitrile, and that SXR/PXR genes encode the primary species-specific xeno-sensors that mediate the adaptive hepatic response, and may represent the critical biochemical mechanism of human xenoprotection. Expand
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TLDR
A novel nuclear receptor is isolated, termed the steroid and xenobiotic receptor (SXR), which activates transcription in response to a diversity of natural and synthetic compounds, which suggests that broad specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily. Expand
The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.
TLDR
The identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP 3A4 expression is reported. Expand
A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.
TLDR
A potent, nonsteroidal FXR ligand is used to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain that provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis. Expand
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TLDR
It is suggested that FXR (BAR) is the endogenous biliary component that selectively activates the orphan nuclear receptor, FXR, and thus an important regulator of cholesterol homeostasis. Expand
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TLDR
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Stimulation of bile acid 6α-hydroxylation by rifampin
Abstract Background: Rifampin was shown to relieve pruritus in cholestatic liver diseases. There has been much speculation about the origin of pruritus, but it has not yet been comprehensivelyExpand
The lithocholic acid 6 beta-hydroxylase cytochrome P-450, CYP 3A10, is an active catalyst of steroid-hormone 6 beta-hydroxylation.
TLDR
It is established that the substrate specificity of the bile acid hydroxylase CYP 3A10 is not restricted to bile acids, and suggested that CYP3A10 can play a physiologically important role in the metabolism of two classes of endogenous P450 substrates:steroid hormones and biles acids. Expand
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TLDR
The molecular cloning, tissue distribution, and xenobiotic regulation of a rat PXR designated rPXR-1 is described, providing the molecular basis that rats and mice have a similar CYP3A induction profile but differ from humans. Expand
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