Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice)

Background and aims: The herbal supplement Gancao, also known as licorice, belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect. Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor (PXR)mediated induction of hepatic cytochrome P450 3A4 (CYP3A4). The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.Methods: DPX2 cells were used for cell-based PXR reporter assays. The phytochemicals in Gancao extract were identified using a metabolomics approach. The effects of PXR activators identified from in vitro studies were further investigated in PXR- and CYP3A4-humanized mouse models. Results: Gancao was verified to be a PXR-activating herb. Two major phytochemicals in Gancao, glycyrrhizin (GZ) and glycyrrhetinic acid (GA), did not activate PXR in the cell-based reporter assays. However, glabridin was shown to activate PXR in a dose-dependent manner. In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator. Although GA did not active PXR in vitro, it induced CYP3A4 expression in a PXR-dependent manner in the PXR- and CYP3A4-humanized mice. Conclusions: GZ is not a PXR activator. GA could not activate PXR in cell-based reporter assays but it could activate PXR in vivo. Glabridin is a weak PXR activator. This work provides novel insights into the underlying mechanisms of Gancao-related herb-drug interactions via PXR.& COPY; 2022 The Third Affiliated Hospital of Sun Yat-sen University. Publishing services by Elsevier B. V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).