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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Guggulsterone Activates Multiple Nuclear Receptors and Induces CYP3A Gene Expression through the Pregnane X Receptor

Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas (D.E.B., X.D., B.K., J.L.S.); and Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina (K.L.C., B.G.)

Gugulipid is an extract of the guggul tree, Commiphora mukul, that is used to treat hyperlipidemia in humans. The lipid-lowering activity is found in the stereoisomers and plant sterols Z-guggulsterone and E-guggulsterone. The molecular basis for the lipid-lowering action of guggulsterone has been suggested to be antagonism of the farnesoid X receptor, a member of the nuclear receptor superfamily of ligand-activated transcription factors. To determine whether guggulsterone has the ability to function as an agonist of other nuclear receptor family members, we screened a panel of these proteins for their ability to transactivate reporter genes. Here, we show that guggulsterones activate the estrogen receptor isoform, progesterone receptor, and pregnane X receptor. Concentration-response analysis using reporter gene assays indicate that guggulsterones activate these three receptors with EC₅₀ values in the low micromolar range. Furthermore, we show that guggulsterone-mediated activation of the pregnane X receptor induces the expression of CYP3A genes in both rodent and human hepatocytes. Protein interaction assays indicate that guggulsterones interact directly with pregnane X receptor, thereby modulating interaction with protein cofactors. We introduce a novel method to screen herbal remedies for their ability to activate pregnane X receptor. Pregnane X receptor activation is known to cause herb-drug interactions, and our data suggest that gugulipid therapy should be used cautiously in patients taking prescription medications that are metabolized by CYP3A family members. Moreover, our data suggest the need for additional studies of guggulsterones agonist activity against estrogen receptor isoform and the progesterone receptor.

Address correspondence to: Dr. Jeff L. Staudinger, Department of Pharmacology and Toxicology, University of Kansas, 5046 Malott Hall, Lawrence, KS 66045. E-mail: stauding{at}ku.edu

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