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

  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 K I MacKenzie and Anne M. Latour and Yaping Liu and Curtis D. Klaassen and Kathleen K. Brown and J Reinhard and Timothy Mark Willson and Beverly H. Koller and Steven A. Kliewer},
  journal={Proceedings of the National Academy of Sciences of the United States of America},
  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… 

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Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor.

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.

Intestinal Detoxification Limits the Activation of Hepatic Pregnane X Receptor by Lithocholic Acid

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.

Regulation of cyp3a gene transcription by the pregnane x receptor.

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.

The role of pregnane X receptor (PXR) in substance metabolism

The functions of PXR in metabolism of different substances such as glucose, lipid, bile acid, vitamin, minerals, and endocrines are summarized and insights of the application of P XR ligands (drugs) in specific diseases are included.

Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor.

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.

The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.

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.


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.

Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice

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.

Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites.

  • J. SonodaL. Chong R. Evans
  • Medicine, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
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.

The xenobiotic receptors PXR and CAR in liver physiology, an update.




The Pregnane X Receptor: A Promiscuous Xenobiotic Receptor That Has Diverged during Evolution

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.

Humanized xenobiotic response in mice expressing nuclear receptor SXR

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.

SXR, a novel steroid and xenobiotic-sensing nuclear receptor.

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.

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.

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.

The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism

It is shown that the nuclear receptor CAR mediates the response evoked by a class of xenobiotics known as the ‘phenobarbital-like inducers’, and loss of CAR function alters sensitivity to toxins, increasing or decreasing it depending on the compound.

The lithocholic acid 6 beta-hydroxylase cytochrome P-450, CYP 3A10, is an active catalyst of steroid-hormone 6 beta-hydroxylation.

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.

Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation.

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.