Structural Basis of Human Pregnane X Receptor Activation by the Hops Constituent Colupulone

Abstract

Hops extracts are used to alleviate menopausal symptoms and as an alternative to hormone replacement therapy, but they can produce potentially harmful drug-drug interactions. The nuclear xenobiotic receptor pregnane X receptor (PXR) is promiscuously activated by a range of structurally distinct chemicals. It has a key role in the transcriptional regulation of genes that encode xenobiotic metabolism enzymes. In this study, hops extracts are shown to induce the expression of numerous drug metabolism and excretion proteins. The ␤-bitter acid colupulone is demonstrated to be a bioactive component and direct activator of human PXR. The 2.8-Å resolution crystal structure of the ligand binding domain of human PXR in complex with colupulone was elucidated, and colupulone was observed to bind in a single orientation stabilized by both van der Waals and hydrogen bonding contacts. The crystal structure also indicates that related ␣-and ␤-bitter acids have the capacity to serve as PXR agonists as well. Taken together, these results reveal the structural basis for drug-drug interactions mediated by colupulone and related constituents of hops extracts.

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

“…It has been shown that an ethanolic extract of hops of unknown chemical composition increases PXR-mediated transcriptional activity (46), as assessed in an in vitro cellbased luciferase reporter gene assay (Table I). Comparative analysis indicates that the extent of PXR activation by the ethanolic extract of hops is similar to that obtained with St. John's wort and Gugulipid®.…”

No Activation of Human Pregnane X Receptor by Hyperforin-Related Phloroglucinols

“…Structure-based methods such as docking enable one to determine whether molecules will fit and have favorable interactions in crystal structures and homology models. Both of these approaches have been widely used for identifying PXR agonists and antagonists (Ekins et al, 2007(Ekins et al, , 2008aYasuda et al, 2008;Biswas et al, 2009;Kortagere et al, 2009Kortagere et al, , 2012Li et al, 2013) for which crystal structures exist (Watkins et al, 2001(Watkins et al, , 2002(Watkins et al, , 2003aChrencik et al, 2005;Noble et al, 2006;Xue et al, 2007a,b;Teotico et al, 2008). The Fig.…”

“…This could also explain why Hyp3 was frequently retrieved by both pharmacophores and docking. It is widely known from our previous work and the many crystal structures (Watkins et al, 2001(Watkins et al, , 2002(Watkins et al, , 2003aChrencik et al, 2005;Noble et al, 2006;Xue et al, 2007a,b;Teotico et al, 2008) that hydrophobicity is important for interaction in the LBD and at the SRC-1 antagonist site (Ekins et al, 2007). The majority of the phloroglucinol derivatives were found to have docking scores lower than the comparator compounds hyperforin and ketoconazole, suggesting that they were unlikely to behave as agonists or antagonists, respectively.…”

Pregnane X Receptor in Drug Development

“…The hops constituent colupulone forms hydrogen bonds with His407 and bonds to Gln285 through a water molecule (Fig. 3F) (Teotico et al 2008). The PXR-ligand interaction appears to be a dynamic process, leading to structural changes that quite possibly alter the interaction between PXR and its coactivator or corepressor.…”