Functional evolution of the pregnane X receptor.
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.
Iyer
Manisha
M
Department of Pathology, University of Pittsburgh, Scaife Hall S-730, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
Reschly
Erica J
EJ
Krasowski
Matthew D
MD
D000595:Amino Acid Sequence; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D000077297:Pregnane X Receptor; D011487:Protein Conformation; D011987:Receptors, Steroid / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014982:Xenopus laevis / Q000378:metabolism
D001647:Bile Acids and Salts; D012739:Gonadal Steroid Hormones; D008024:Ligands; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A