Regulation of CYP3A Gene Transcription by the Pregnane X Receptor

Annual Review of Pharmacology and Toxicology

Vol. 42:1-23 (Volume publication date April 2002)


The pregnane X receptor (PXR) is a promiscuous nuclear receptor that has evolved to protect the body from toxic chemicals. PXR is activated by a structurally diverse collection of xenobiotics, including several widely used prescription drugs. Various lipophilic compounds produced by the body, such as bile acids and steroids, also activate PXR. PXR stimulates the transcription of cytochrome P450 3A monooxygenases and other genes involved in the detoxification and elimination of these potentially harmful chemicals. Assays that detect PXR activation have important implications for the design of future drugs in two respects. On the one hand, PXR activation assays can be used to determine whether candidate drugs are likely to induce CYP3A gene expression and interact with other medicines. On the other hand, PXR agonists may prove useful in the treatment of diseases in which toxic metabolites accumulate, such as cholestatic liver disease.


*ABBREVIATIONS CYP, cytochrome P450; PXR, pregnane X receptor; PCN, pregnenolone 16α-carbonitrile; LCA, lithocholic acid; ER6, everted repeat with a 6 nucleotide spacer; DRn, direct repeat with a n nucleotide spacer; DBD, DNA-binding domain; LBD, ligand-binding domain; CAR, constitutive androstane receptor; SPA, scintillation proximity assay; RXRα, 9-cis retinoic acid receptor α; XREM, xenobiotic-responsive enhancer module.