No activation of human PXR by hyperforin-related phloroglucinols


The acylated phloroglucinol, hyperforin, the main active ingredient of St John's wort, exerts anti-depressant properties via indirect inhibition of serotonin reuptake by selectively activating the canonical transient receptor potential channel 6 (TRPC6). Hyperforin treatment can lead to drug-drug interactions due to potent activation of the nuclear receptor PXR (NR1I2), a key transcriptional regulator of genes involved in drug metabolism and transport. It was previously shown that synthetic acylated phloroglucinol derivatives activate TRPC6 with similar potency as hyperforin. However, their interaction potential with PXR remained unknown. Here we investigated five synthetic TRPC6 activating phloroglucinol derivatives and four TRPC6 non-activating compounds in comparison to hyperforin and rifampicin for their potential to activate PXR in silico and in vitro. Computational PXR pharmacophore modeling did not indicate potent agonist or antagonist interactions for the TRPC6 activating derivatives while one of them was suggested by docking studies to show both agonist and antagonist interactions. Hyperforin and rifampicin treatment of HepG2 cells co-transfected with human PXR expression-vector and a CYP3A4 promoter-reporter construct resulted in potent PXR-dependent induction, while all TRPC6 activating compounds failed to show any PXR activation or to antagonize rifampicin-mediated CYP3A4 promoter induction. Hyperforin and rifampicin treatment of primary human hepatocytes resulted in highly correlated induction of PXR-target genes, whereas treatment with the phloroglucinol derivatives elicited moderate gene expression changes only weakly correlated to those of rifampicin and hyperforin treatment. These results show that TRPC6-activating phloroglucinols do not activate PXR and should therefore be promising new candidates for further drug development.


Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes

J. Pharmacol. Exp. Ther.
J. Pharmacol. Exp. Ther. :
22nd Nov 2013

Benjamin A Kandel, Sean Ekins, Kristina Leuner, Wolfgang E Thasler, Christian Harteneck, Ulrich M Zanger

help Authors

[Benjamin Kandel] [Wolfgang E. Thasler] [Ulrich Zanger]

help Attributions


help Scales

Not Specified
Views: 2105
  • Created: 8th Jan 2014 at 13:53

Related items


Log in / Register

Need an account?
Sign up

Forgotten password?

Front Page

Virtual Liver Network


Related Projects and friends

Imprint Taverna workflow workbench myExperiment JWS Online ISATAB myGrid Sabio-RK BioPortal Semantic SBML

Powered by:


Silk icons 1.3
Crystal Clear icons

Virtual Liver Seek uses one essential cookie to keep you session open and one cookie to keep your consent.

By continuing to use this site you agree to the use of cookies