Orphan receptor promiscuity in the induction of cytochromes p450 by xenobiotics.
The mechanisms by which different classes of chemicals induce the same cytochrome P450 (CYP) or the same chemical differentially induces more than one CYP are not well understood. We show that in primary hepatocytes and in vivo in liver (transfected by particle-mediated delivery) two orphan nuclear receptors, constitutive androstane receptor and pregnane X receptor (PXR1), transactivate a CYP gene via the same response element in a xenobiotic-specific manner. The constitutive androstane receptor mediates the barbiturate activation of expression of CYP2B1 and CYP3A1. PXR1 activates both genes in response to synthetic steroids. To exert their effect the receptors bind to the same direct repeat site (DR4) within the phenobarbital response element of the CYP2B1 promoter and to the same DR3 site in the pregnane X response element of CYP3A1. The receptors are therefore promiscuous with respect to DNA binding but not ligand binding. Differences in enhancer half-site spacing may influence the efficiency of interactions between the receptor and the transcription machinery and hence form the basis for the differential induction of CYP2B1 and CYP3A1 in response to barbiturates and synthetic steroids.
Smirlis
D
D
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Muangmoonchai
R
R
Edwards
M
M
Phillips
I R
IR
Shephard
E A
EA
D000818:Animals; D019470:Biolistics; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D019281:Dimerization; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D047488:Retinoid X Receptors; D012455:Salamandridae; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D015262:Xenobiotics / Q000494:pharmacology*
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D015500:Chloramphenicol O-Acetyltransferase