title: TO901317, a potent LXR agonist, is an inverse agonist of CAR.
abstract: The basal transcriptional activity of unliganded human constitutive androstane receptor (hCAR) was shown to be repressed by the potent liver X receptor (LXR) agonist, TO901317, in a concentration-dependent manner using a reporter assay in cultured cells. TO901317 also repressed the basal transcriptional activity of both mouse and rat CAR. The certified hCAR agonist, CITCO, partially reversed this repressive effect of TO901317 on hCAR basal activity. Unlike hCAR, a three alanine insertion mutant and the splice variant 2 of hCAR require agonists, such as CITCO, to become transcriptionally active and the CITCO-induced reporter activity was repressed by TO901317. As has been previously shown for the typical hCAR inverse agonist, PK11195, TO901317 blocked the interaction of hCAR with steroid receptor co-activator 1 (SRC1). In contrast, the interaction between hCAR and nuclear receptor corepressor 1 (NCoR1) was promoted by PK11195 and TO901317. Furthermore, the hCAR-mediated basal induction of endogenous cytochrome P450 2B6 (CYP2B6) mRNA was adversely affected by co-treatment with TO901317.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kanno
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Tanuma
authors.forename: Ami
authors.initials: A
authors.lastname: Takahashi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Inouye
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D004790:Enzyme Induction / Q000187:drug effects; D014644:Genetic Variation; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000009:adverse effects / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D056920:Nuclear Receptor Coactivator 1 / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics* / Q000502:physiology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D056920:Nuclear Receptor Coactivator 1; D057093:Orphan Nuclear Receptors; D010089:Oxidoreductases, N-Demethylating; D010091:Oximes; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D013844:Thiazoles; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C475093:6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime; C585599:CYP2B6 protein, human