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Regulation of human pregnane X receptor and its target gene cytochrome P450 3A4 by Chinese herbal compounds and a molecular docking study
journal contribution
posted on 2011-04-01, 00:00 authored by Y H Liu, S L Mo, H C Bi, B F Hu, C Li, Y T Wang, L Huang, M Huang, Wei DuanWei Duan, J P Liu, M Wei, S F Zhou1. The pregnane X receptor (PXR) plays a critical role in the regulation of human cytochrome P450 3A4 (CYP3A4) gene. In this study, we investigated the effect of an array of compounds isolated from Chinese herbal medicines on the activity of PXR using a luciferase reporter gene assay in transiently transfected HepG2 and Huh7 cells and on the expression of PXR and CYP3A4 in LS174T cells. Furthermore, molecular docking was performed to investigate the binding modes of herbal compounds with PXR.
2. Praeruptorin A and C, salvianolic acid B, sodium danshensu, protocatechuic aldehyde, cryptotanshinone, emodin, morin, and tanshinone IIA significantly transactivated the CYP3A4 reporter gene construct in either HepG2 or Huh7 cells. The PXR mRNA expression in LS174T cells was significantly induced by physcion, protocatechuic aldehyde, salvianolic acid B, and sodium danshensu. However, epifriedelanol, morin, praeruptorin D, mulberroside A, tanshinone I, and tanshinone IIA significantly down-regulated the expression of PXR mRNA in LS174T cells.
3. All the herbal compounds tested can be readily docked into the ligand-binding cavity of PXR mainly through hydrogen bond and aromatic interactions with Ser247, Gln285, His407, and Arg401.
4. These findings suggest that herbal medicines can significantly regulate PXR and CYP3A4 and this has important implication in herb–drug interactions.
2. Praeruptorin A and C, salvianolic acid B, sodium danshensu, protocatechuic aldehyde, cryptotanshinone, emodin, morin, and tanshinone IIA significantly transactivated the CYP3A4 reporter gene construct in either HepG2 or Huh7 cells. The PXR mRNA expression in LS174T cells was significantly induced by physcion, protocatechuic aldehyde, salvianolic acid B, and sodium danshensu. However, epifriedelanol, morin, praeruptorin D, mulberroside A, tanshinone I, and tanshinone IIA significantly down-regulated the expression of PXR mRNA in LS174T cells.
3. All the herbal compounds tested can be readily docked into the ligand-binding cavity of PXR mainly through hydrogen bond and aromatic interactions with Ser247, Gln285, His407, and Arg401.
4. These findings suggest that herbal medicines can significantly regulate PXR and CYP3A4 and this has important implication in herb–drug interactions.
History
Journal
XenobioticaVolume
41Issue
4Pagination
259 - 280Publisher
Informa HealthcareLocation
London, U. K.Publisher DOI
ISSN
0049-8254eISSN
1366-5928Language
engPublication classification
C1 Refereed article in a scholarly journal; C Journal articleCopyright notice
2011, Informa UK, Ltd.Usage metrics
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PXRCYP3A4inductionherbal medicineherb–drug interactionScience & TechnologyLife Sciences & BiomedicinePharmacology & PharmacyToxicologyherb-drug interactionCONSTITUTIVE ANDROSTANE RECEPTORPRIMARY HUMAN HEPATOCYTESCOREPRESSOR SILENCING-MEDIATORHEPATOMA-CELL LINESHUMAN CYP3A4 GENENUCLEAR RECEPTORDRUG-METABOLISMTRANSCRIPTIONAL ACTIVATIONXENOBIOTIC RECEPTORINTERINDIVIDUAL VARIABILITY
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