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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 15, 2005; DOI: 10.1124/jpet.105.085225

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Received for publication February 22, 2005.
Revised April 12, 2005.
Accepted for publication April 13, 2005.

The Ratio of CAR to PXR Determines the Activity of Guggulsterone against the Cyp2b10 Promoter

Xunshan Ding 1 Jeffrey L Staudinger 1*

1 University of Kansas

* Address correspondence to: E-mail: stauding{at}ku.edu

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, NR1I3) ligand. We show here 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-KO). We also show that PXR-CAR crosstalk 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 insights into the molecular mechanism of inter-individual 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 anti-obesity drugs.


Key words: CAR, Cyp2b10, PXR, guggulsterone, gugulipid, obesity


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