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 ...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 P4503A4(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,gly-cyrrhizin(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.展开更多
Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in dru...Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small molecules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.展开更多
基金This work was supported by the USA National Center for Com-plementary and Integrative Health Grant R21AT011088(to X.Ma)in part by Grant U54AT008909(to M.F.Paine)+1 种基金in part by the USA National Institute of Allergy and Infectious Diseases Grant R01AI131983(to X.Ma)National Institute of Diabetes and Digestive and Kidney Diseases Grant R01DK126875(to X.Ma).
文摘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 P4503A4(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,gly-cyrrhizin(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.
基金supported,in part,by ALSAC and by the National Institutes of Health grants R35-GM118041 and P30-CA21765.
文摘Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small molecules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.
