The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic Metabolism
The nuclear pregnane X receptor (PXR; NR1I2) is an important component of the body's adaptive defense mechanism against toxic substances including foreign chemicals (xenobiotics). PXR is activated by a large number of endogenous and exogenous chemicals including steroids, antibiotics, antimycotics, bile acids, and the herbal antidepressant St. John's wort. Elucidation of the three-dimensional structure of the PXR ligand binding domain revealed that it has a large, spherical ligand binding cavity that allows it to interact with a wide range of hydrophobic chemicals. Thus, unlike other nuclear receptors that interact selectively with their physiological ligands, PXR serves as a general-ized sensor of hydrophobic toxins. PXR binds as a heterodimer with the 9-cis retinoic acid receptor (NR2B) to DNA response elements in the regulatory regions of cytochrome P450 3A monooxygenase genes and a number of other genes involved in the metabolism and elimination of xenobiotics from the body. 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. Thus, assays that detect PXR activity will be useful in developing safer prescription drugs. ( Regulation of CYP3A by Xenobiotics A. Induction of CYP3A by structurally diverse compounds B. Xenobiotic response elements in CYP3A promoters III. Cloning and Characterization of PXR A. Cloning of PXR B. PXR expression pattern C. Activation of PXR by xenobiotics and natural steroids D. Ligand binding properties of PXR E. DNA binding properties of PXR F. PXR polymorphisms IV. Function of PXR in Vivo A. PXR-null mice B. Humanized PXR mice C. PXR target genes D. PXR as a basis for drug interactions V. PXR and Bile Acid Metabolism VI. PXR Cross-Talk with CAR VII. Structure of the PXR Ligand Binding