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)-med...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2022-12-01
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| Series: | Liver Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S254256842200068X |
| _version_ | 1797975206235471872 |
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| author | Anqi Cheng Saifei Lei Junjie Zhu Jie Lu Mary F. Paine Wen Xie Xiaochao Ma |
| author_facet | Anqi Cheng Saifei Lei Junjie Zhu Jie Lu Mary F. Paine Wen Xie Xiaochao Ma |
| author_sort | Anqi Cheng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T04:31:49Z |
| format | Article |
| id | doaj.art-b8cfc72ec847483fa6c29ed759363669 |
| institution | Directory Open Access Journal |
| issn | 2542-5684 |
| language | English |
| last_indexed | 2024-04-11T04:31:49Z |
| publishDate | 2022-12-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Liver Research |
| spelling | doaj.art-b8cfc72ec847483fa6c29ed7593636692022-12-29T04:13:51ZengKeAi Communications Co., Ltd.Liver Research2542-56842022-12-0164251257Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice)Anqi Cheng0Saifei Lei1Junjie Zhu2Jie Lu3Mary F. Paine4Wen Xie5Xiaochao Ma6Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USACenter for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USACenter for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USACenter for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USADepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USACenter for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USACenter for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author. Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.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.http://www.sciencedirect.com/science/article/pii/S254256842200068XGancaoLicoriceGlabridinPregnane X receptor (PXR)Cytochrome P450 3A4 (CYP3A4)Herb-drug interactions |
| spellingShingle | Anqi Cheng Saifei Lei Junjie Zhu Jie Lu Mary F. Paine Wen Xie Xiaochao Ma Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice) Liver Research Gancao Licorice Glabridin Pregnane X receptor (PXR) Cytochrome P450 3A4 (CYP3A4) Herb-drug interactions |
| title | Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice) |
| title_full | Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice) |
| title_fullStr | Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice) |
| title_full_unstemmed | Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice) |
| title_short | Chemical basis of pregnane X receptor activators in the herbal supplement Gancao (licorice) |
| title_sort | chemical basis of pregnane x receptor activators in the herbal supplement gancao licorice |
| topic | Gancao Licorice Glabridin Pregnane X receptor (PXR) Cytochrome P450 3A4 (CYP3A4) Herb-drug interactions |
| url | http://www.sciencedirect.com/science/article/pii/S254256842200068X |
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