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J Pharmacol Exp Ther. 2014 Mar;348(3):393-400. doi: 10.1124/jpet.113.209916. Epub 2013 Nov 20.

No activation of human pregnane X receptor by hyperforin-related phloroglucinols.

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Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (B.A.K., U.M.Z.); University of Tübingen, Tübingen, Germany (B.A.K., U.M.Z.); Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (S.E.); Department of Pharmacology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, New Jersey (S.E.); Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (S.E.); Molecular and Clinical Pharmacy, Friedrich-Alexander University, Erlangen-Nuremberg, Germany (K.L.); Department of Surgery, Grosshadern Hospital, Ludwig-Maximilians University, Munich, Germany (W.E.T.); and Institute of Pharmacology and Toxicology, Interfaculty Centre for Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany (C.H.).


The acylated phloroglucinol, hyperforin, the main active ingredient of St. John's Wort, exerts antidepressant 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-nonactivating compounds compared with 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, whereas one of them was suggested by docking studies to show both agonist and antagonist interactions. Hyperforin and rifampicin treatment of HepG2 cells cotransfected with human PXR expression vector and a CYP3A4 promoter-reporter construct resulted in potent PXR-dependent induction, whereas 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 that were only weakly correlated with 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.

[Indexed for MEDLINE]

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