Identification of PXR Activators from (Gou Teng) and (Cat's Claw)

DOI

10.1124/dmd.122.001234

Saifei Lei, Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (S.L., J.L., A.C., Z.H., J.Z., X.M.) and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (K.T.).
Jie Lu, Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (S.L., J.L., A.C., Z.H., J.Z., X.M.) and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (K.T.).
Anqi Cheng, Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (S.L., J.L., A.C., Z.H., J.Z., X.M.) and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (K.T.).
Zahir Hussain, Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (S.L., J.L., A.C., Z.H., J.Z., X.M.) and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (K.T.).
Kevin Tidgewell, Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (S.L., J.L., A.C., Z.H., J.Z., X.M.) and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (K.T.).
Junjie Zhu, Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (S.L., J.L., A.C., Z.H., J.Z., X.M.) and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (K.T.) juz28@pitt.edu mxiaocha@pitt.edu.
Xiaochao Ma, Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (S.L., J.L., A.C., Z.H., J.Z., X.M.) and Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (K.T.) juz28@pitt.edu mxiaocha@pitt.edu.

Document Type

Journal Article

Publication Date

5-1-2023

Publication Title

Drug metabolism and disposition: the biological fate of chemicals

Volume

51

Issue

5

First Page

629

Last Page

636

Abstract

(Gou Teng) and (cat's claw) are frequently used herbal supplements in Asia and America, respectively. Despite their common usage, information is limited regarding potential herb-drug interactions associated with Gou Teng and cat's claw. The pregnane X receptor (PXR) is a ligand-dependent transcription factor that regulates cytochrome P450 3A4 (CYP3A4) expression and contributes to some known herb-drug interactions. A recent study found that Gou Teng induces CYP3A4 expression, but its mechanism is unknown. Cat's claw has been determined as a PXR-activating herb, but the PXR activators in cat's claw have not been identified. Using a genetically engineered PXR cell line, we found that the extracts of Gou Teng and cat's claw can dose-dependently activate PXR and induce CYP3A4 expression. We next used a metabolomic approach to profile the chemical components in the extracts of Gou Teng and cat's claw followed by screening for PXR activators. Four compounds, isocorynoxeine, rhynchophylline, isorhynchophylline, and corynoxeine, were identified as PXR activators from both Gou Teng and cat's claw extracts. In addition, three more PXR activators were identified from the extracts of cat's claw, including isopteropodine, pteropodine, and mitraphylline. All seven of these compounds showed the half-maximal effective concentration <10 µM for PXR activation. In summary, our work determined Gou Teng as a PXR-activating herb and discovered novel PXR activators from Gou Teng as well as cat's claw. SIGNIFICANCE STATEMENT: This study's data can be used to guide the safe use of Gou Teng and cat's claw by avoiding PXR-mediated herb-drug interactions.

Open Access

36797057 (pubmed); PMC10158501 (pmc); 10.1124/dmd.122.001234 (doi); dmd.122.001234 (pii)

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