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Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, Basel, Switzerland
Induction of drug metabolism was described more than 40 years ago. Progress in understanding the molecular mechanism of induction of drug-metabolizing enzymes was made recently when the important roles of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of transcription factors, were discovered to act as sensors for lipophilic xenobiotics, including drugs. CAR and PXR bind as heterodimeric complexes with the retinoid X receptor to response elements in the regulatory regions of the induced genes. PXR is directly activated by xenobiotic ligands, whereas CAR is involved in a more complex and less well understood mechanism of signal transduction triggered by drugs. Most recently, analysis of these xenobiotic-sensing nuclear receptors and their nonmammalian precursors such as the chicken xenobiotic receptor suggests an important role of PXR and CAR also in endogenous pathways, such as cholesterol and bile acid biosynthesis and metabolism. In this review, recent findings regarding xenosensors and their target genes are summarized and are put into an evolutionary perspective in regard to how a living organism has derived a system that is able to deal with potentially toxic compounds it has not encountered before.
Abstract I. Introduction II. Drug-Mediated Induction of Cytochromes P450 A. Induction of CYP2Bs, CYP2Cs, and CYP3As by Drugs and Xenobiotics III. Drug-Response Elements in Inducible Cytochrome P450 Genes A. CYP102/106 in Bacillus megaterium B. CYP6 in Insects C. CYP2H1/2, CYP3A37, and CYP2C45 in Chicken D. CYP2Bs, CYP3As, and CYP2Cs in Mammals E. Other Mammalian Drug-Inducible Cytochromes P450 IV. Nuclear Receptors Involved in Drug Induction of Cytochromes P450 A. Constitutive Androstane Receptor B. Pregnane X Receptor C. The Evolution of Xenosensors: Lessons Learned from the Chicken Xenobiotic Receptor D. Structure of the Xenosensors E. Other Target Genes of Pregnane X Receptor and Constitutive Androstane Receptor V. Endogenous Roles of the Xenosensors A. Receptor Cross Talk in Hepatic Drug Induction VI. Clinical Relevance of Induction A. Altered Kinetics of Drugs B. Genetic Variants of Pregnane X Receptor and Constitutive Androstane Receptor VII. Open Questions A. Mechanisms of Constitutive Androstane Receptor Translocation and Activation B. Cofactors Involved in Pregnane X Receptor- and Constitutive Androstane Receptor-Mediated Signal Transduction C. The Xenosensors as Drug Targets D. The Mystery of How Cells Recognize Phenobarbital-Type Inducers VIII. Outlook
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