title: Modulation of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) by 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives, ligands of peripheral benzodiazepine receptor (PBR).
abstract: Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate xenobiotic sensing and metabolism through interactions with multiple exogenous and endogenous chemicals. Compounds that activate CAR are often ligands of PXR; attention is therefore given to discovery of new, receptor-specific chemical entities that may be exploited for therapeutic and basic research purposes. Recently, ligands of the peripheral benzodiazepine receptor (PBR), PK11195 and FGIN-1-27, were shown to modulate both CAR and PXR. PBR is a mitochondrial transport protein responsible for multiple regulatory functions, including heme biosynthesis, a major component in cytochrome P450 (CYP) enzymes. To investigate possible new roles for PBR involvement in metabolic regulation, expression of the CAR and PXR target genes, CYP2B6 and CYP3A4, was measured in human hepatocytes following treatment with a targeted PBR ligand set. Luciferase reporter assays with transiently expressed wild-type CAR (CAR1), splice variant CAR3, or PXR in HuH-7 cells were used to further study activation of these receptors. Four structurally related PBR ligands (benzothiazepines) differentially modulate CAR1, CAR3 and PXR activity. Benzothiazepine NF49 is an agonist ligand of CAR3, a partial agonist of PXR, exhibits greater inverse agonist activity on CAR1 than does PK11195, and is a new tool for studying these closely related nuclear receptors.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, and Center for Molecular Toxicology, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, United States.
authors.forename: Linnea E
authors.initials: LE
authors.lastname: Anderson
authors.forename: Ann M
authors.initials: AM
authors.lastname: Dring
authors.forename: Laura D
authors.initials: LD
authors.lastname: Hamel
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Stoner
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D011758:Pyrroles / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D011987:Receptors, Steroid / Q000819:agonists / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013841:Thiazepines / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000090702:Constitutive Androstane Receptor; D007210:Indoleacetic Acids; D007546:Isoquinolines; D000077297:Pregnane X Receptor; D011758:Pyrroles; D018160:Receptors, Cytoplasmic and Nuclear; D011963:Receptors, GABA-A; D011987:Receptors, Steroid; D013841:Thiazepines; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D012313:RNA; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; C037850:PK 11195