Bioactive Terpenoids and Flavonoids from Ginkgo Biloba Extract Induce the Expression of Hepatic Drug-Metabolizing Enzymes Through Pregnane X Receptor,Constitutive Androstane Receptor,and Aryl hydrocarbon Receptor-Mediated Pathways |
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Authors: | Linhao Li Joseph D Stanton Antonia H Tolson Yuan Luo Hongbing Wang |
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Institution: | (1) Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, Baltimore, Maryland 21201, USA |
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Abstract: | Purpose The objective of the current study is to investigate the hypothesis that bioactive terpenoids and flavonoids of Ginkgo biloba
extract (GBE) induce human hepatic drug metabolizing enzymes (DMEs) and transporters through the selective activation of pregnane
X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR).
Methods Human primary hepatocyte (HPH), and HepG2 cells are used as in vitro models for enzyme induction and nuclear receptor activation studies. A combination of real-time RT-PCR, transient transfection,
and cell-based reporter assays were employed.
Results In human primary hepatocytes, real-time PCR analysis showed induction of CYP2B6, CYP3A4, UGT1A1, MDR1, and MRP2 by EGb 761,
ginkgolide A (GA) and ginkgolide B (GB), but not by bilobalide (BB) or the flavonoids (quercetin, kaempferol and tamarixetin)
of GBE. Cell-based reporter assays in HepG2 revealed that GA and GB are potent activators of PXR; quercetin and kaempferol
activate PXR, CAR, and AhR, whereas BB exerts no effects on these xenobiotic receptors. Notably, the flavonoids induced the
expression of UGT1A1 and CYP1A2 in HepG2 cells but not in HPH.
Conclusion Our results indicate that terpenoids and flavonoids of GBE exhibit differential induction of DMEs through the selective activation
of PXR, CAR, and AhR. |
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Keywords: | AhR CAR cytochrome P450 EGb 761 PXR |
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