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 generalized 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.
Kliewer
Steven A
SA
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. steven.kliewer@utsouthwestern.edu
Goodwin
Bryan
B
Willson
Timothy M
TM
D000595:Amino Acid Sequence; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism; D001665:Binding Sites; D002467:Cell Nucleus / Q000737:chemistry*; D003001:Cloning, Molecular; D051544:Cytochrome P-450 CYP3A; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011987:Receptors, Steroid / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020218:Response Elements; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism* / Q000494:pharmacology
D001647:Bile Acids and Salts; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D015262:Xenobiotics; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating