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

Abstract

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 lipidlowering 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 EC 50 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.

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

“…The pharmacological activity of phytosterols has been shown to be mediated by the antagonism of the nuclear receptor and a ligand for multiple nuclear receptors [162]. Brobst et al showed that phytosterols activate the estrogen receptor an isoform, progesterone receptor, and pregnane X receptor (PXR, NR1I2) [162]. They also showed that phytosterol-mediated activation of PXR induces the expression of drug-metabolizing enzyme cytochrome P450 (CYP) CYP3A gene.…”

“…Additionally, we reported that β-sitosterol-O-glucoside is more effective than stigmasterol in interacting with cell membrane proteins and in reversal of doxorubicin resistance [64]. The pharmacological activity of phytosterols has been shown to be mediated by the antagonism of the nuclear receptor and a ligand for multiple nuclear receptors [162]. Brobst et al showed that phytosterols activate the estrogen receptor an isoform, progesterone receptor, and pregnane X receptor (PXR, NR1I2) [162].…”

Pregnane X receptor and natural products: beyond drug–drug interactions

“…More importantly, both gugulipid and guggulsterone treatments induce the gene expression of CYP3A4 in primary human hepatocytes. Mammalian-two-hybrid and glutathione S-transferase-pull-down assays demonstrate that guggulsterone activates PXR by recruiting the coactivator SRC-1 [38]. These findings raise the issue that, in addition to its desirable effects on lipid disorders, gugulipid may cause serious drug interactions in humans on combination therapy through activation of PXR.…”

“…In addition to farnesoid X receptor and PXR, studies have shown that guggulsterones modulate the activity of multiple receptors, including the constitutive androstane receptor (CAR), glucocorticoid receptor, progesterone receptor, mineralocorticoid receptor, androgen receptor and estrogen receptor [38,39,41]. These investigations suggest that further studies of gugulipid and guggulsterones are needed to explore the biological functions of this important herbal remedy.…”

“…Recent work from Brobst et al shows that guggulsterones are efficacious PXR agonists [38]. Both gugulipid and guggulsterones activate PXR in reporter gene assays.…”