Functional evolution of the pregnane X receptor

Manisha Iyer; Erica J Reschly; Matthew D Krasowski

doi:10.1517/17425255.2.3.381

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Functional evolution of the pregnane X receptor

Journal article

Open access

Peer reviewed

Functional evolution of the pregnane X receptor

Manisha Iyer, Erica J Reschly and Matthew D Krasowski

Expert opinion on drug metabolism & toxicology, Vol.2(3), pp.381-397

06/2006

DOI: 10.1517/17425255.2.3.381

PMCID: PMC2231407

PMID: 16863441

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https://www.ncbi.nlm.nih.gov/pmc/articles/2231407View

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Abstract

The pregnane X receptor (PXR; NR1I2) is a nuclear hormone receptor (NR) that transcriptionally regulates genes encoding transporters and drug-metabolising enzymes in the liver and intestine. PXR activation leads to enhanced metabolism and elimination of xenobiotics and endogenous compounds such as hormones and bile salts. Relative to other vertebrate NRs, PXR has the broadest specificity for ligand activators by virtue of a large, flexible ligand-binding cavity. In addition, PXR has the most extensive sequence diversity across vertebrate species in the ligand-binding domain of any NR, with significant pharmacological differences between human and rodent PXRs, and especially marked divergence between mammalian and nonmammalian PXRs. The unusual properties of PXR complicate the use of in silico and animal models to predict in vivo human PXR pharmacology. Research into the evolutionary history of the PXR gene has also provided insight into the function of PXR in humans and other animals.

Intestines - drug effects

Bile Acids and Salts - pharmacology

Liver - enzymology

Receptors, Steroid - metabolism

Species Specificity

Humans

Molecular Sequence Data

Phylogeny

Receptors, Steroid - agonists

Cytochrome P-450 CYP3A - genetics

Liver - drug effects

Computer Simulation

Cytochrome P-450 CYP3A - chemistry

Amino Acid Sequence

Drug Evaluation, Preclinical - methods

Gonadal Steroid Hormones - pharmacology

Models, Molecular

Receptors, Steroid - chemistry

Gene Expression Regulation, Enzymologic

Animals

Receptors, Steroid - genetics

Cytochrome P-450 CYP3A - metabolism

Xenopus laevis - metabolism

Ligands

Protein Conformation

Mutation

Evolution, Molecular

Intestines - enzymology

Details

Title: Subtitle: Functional evolution of the pregnane X receptor
Creators: Manisha Iyer - Department of Pathology, University of Pittsburgh, Scaife Hall S-730, 3550 Terrace Street, Pittsburgh, PA 15261, USA
Erica J Reschly
Matthew D Krasowski
Resource Type: Journal article
Publication Details: Expert opinion on drug metabolism & toxicology, Vol.2(3), pp.381-397
DOI: 10.1517/17425255.2.3.381
PMID: 16863441
PMCID: PMC2231407
NLM abbreviation: Expert Opin Drug Metab Toxicol
ISSN: 1742-5255
eISSN: 1744-7607
Publisher: England
Grant note: K08 GM074238-01A1 / NIGMS NIH HHS K08 GM074238 / NIGMS NIH HHS K08-GM074238-01A1 / NIGMS NIH HHS
Language: English
Date published: 06/2006
Academic Unit: Pathology
Record Identifier: 9984047659202771

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