title: The ratio of constitutive androstane receptor to pregnane X receptor determines the activity of guggulsterone against the Cyp2b10 promoter.
abstract: Guggulsterone is the active ingredient in gugulipid, an organic extract of the Commiphora mukul plant. Gugulipid has been used for nearly 3000 years in Ayurvedic medicine, mainly as a treatment for arthritis. Herbal practitioners currently use gugulipid therapy in conditions as diverse as rheumatism, coronary artery disease, arthritis, hyperlipidemia, acne, and obesity. The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand. We show herein that guggulsterone treatment represses the expression of cytochrome P450 2b10 (Cyp2b10) gene expression by inhibiting constitutive androstane receptor (CAR; NR1I3) activity in hepatocytes lacking functional PXR (PXR-knockout). We also show that PXR-CAR cross-talk determines the net activity of guggulsterone treatment toward Cyp2b10 gene expression. Using mammalian two-hybrid assays, we show that treatment with guggulsterone differentially affects protein cofactor recruitment to these two nuclear receptors. These data identify guggulsterone as an inverse agonist of the nuclear receptor CAR. When viewed together with the data showing that PXR and CAR expression is highly variable in different ethnic populations and that CAR expression is under the control of a circadian rhythm, our data provide important insight into the molecular mechanism of interindividual variability of drug metabolism. These data, together with the recent resolution of the crystal structures of PXR and CAR, will likely aid in the rational design of more specific CAR inverse agonists that are currently viewed as potential antiobesity drugs.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Dr., 5046 Malott Hall, Lawrence, KS 66045, USA.
authors.forename: Xunshan
authors.initials: X
authors.lastname: Ding
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Staudinger
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015152:Blotting, Northern; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D000072467:Cytochrome P450 Family 2; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010957:Plasmids / Q000235:genetics; D000077297:Pregnane X Receptor; D011282:Pregnenediones / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics*; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
chemical_list: D000090702:Constitutive Androstane Receptor; C000625853:Nr1i2 protein, mouse; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D011282:Pregnenediones; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C023617:pregna-4,17-diene-3,16-dione; D008156:Luciferases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2