Functional evolution of the pregnane X receptor

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 insilico and animal models to predict invivo 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.

Keywords::

• bile acids and salts
• molecular evolution
• molecular models
• nuclear hormone receptors
• phylogeny
• pregnane X receptor
• steroid receptors

Acknowledgements

MD Krasowski is supported by a Clinical-Scientist Development Award from the National Institutes of Health (K08-GM074238-01A1).