The Orphan Human Pregnane X Receptor Mediates the Transcriptional Activation of CYP3A4 by Rifampicin through a Distal Enhancer Module

• Published in: Molecular pharmacology Vol. 56; no. 6; pp. 1329 - 1339
• Main Authors: Goodwin, Bryan, Hodgson, Ecushla, Liddle, Christopher
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.1999; American Society for Pharmacology and Experimental Therapeutics
• Subjects: 3T3 Cells; Animals; Antibiotics, Antitubercular - pharmacology; Base Sequence; COS Cells; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Deoxyribonuclease I - metabolism; Dimerization; DNA; DNA Footprinting; Enhancer Elements, Genetic; Enzyme Induction; Gene Expression Regulation, Enzymologic - drug effects; Humans; Mice; Mifepristone - pharmacology; Mixed Function Oxygenases - biosynthesis; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Molecular Sequence Data; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, Retinoic Acid - metabolism; Receptors, Steroid - physiology; Retinoic Acid Receptor alpha; Rifampin - pharmacology; Sequence Homology, Nucleic Acid; Transcriptional Activation; Transfection; Tumor Cells, Cultured; Xenobiotics; HNF; RXRα; DMSO; PXR; XREM; P-450; hGR; EMSA; prPXRE; tk; PCN; COUP-TF; GRE; RORα1; PXRE; PCR

Cytochrome P-450 3A4 (CYP3A4), the predominant cytochrome P-450 expressed in adult human liver, is subject to transcriptional induction by a variety of structurally unrelated xenobiotics, including the antibiotic rifampicin. The molecular mechanisms underlying this phenomenon are poorly understood....