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

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. Cellbased 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.

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

“…Consistent with these findings, G. biloba extract is capable of inducing PXR target genes (Table II), including CYP3A4, as shown in PXR-expressing LS180 cells in culture (41) and in primary cultures of human hepatocytes (42). Although ginkgolide A and B have been reported to activate human PXR (42,43), the concentrations used in those cell culture experiments far exceed the levels present in an extract of G. biloba. Thus, it remains to be determined which chemical constituent(s) is responsible for the in vitro activation of PXR by G. biloba extract.…”

“…Detailed dose-response data indicate that the extract is effective in activating human PXR transcriptional activity at concentrations of 100-800 µg/ml (Table I). Activation of human PXR by G. biloba extract was confirmed in a subsequent study (42) ( Table I). Consistent with these findings, G. biloba extract is capable of inducing PXR target genes (Table II), including CYP3A4, as shown in PXR-expressing LS180 cells in culture (41) and in primary cultures of human hepatocytes (42).…”

Inhibition of Intestinal and Hepatic Glucuronidation of Mycophenolic Acid by Ginkgo biloba Extract and Flavonoids

“…First, the study does not rule out the possibility of induction of MPA metabolism by G. biloba. A recent study showed that G. biloba and its components induce cytochrome P450 enzymes, transporters, and UGT1A1 (Li et al, 2009). The effect of G. biloba on MPA-metabolizing enzymes in hepatocytes warrants further research.…”

Antiproliferative effect of the Ginkgo biloba extract is associated with the enhancement of cytochrome P450 1B1 expression in estrogen receptor-negative breast cancer cells

“…However, CYP1B1 is uniquely overexpressed in a wide range of human cancers of different histogenetic types compared to normal tissues (26)(27)(28). Several studies reported that the Ginkgo biloba extract exhibits differential induction of CYPs (29)(30)(31). The aim of this study was to assess whether the Ginkgo biloba extract induces CYP1B1 expression and affects the proliferation of MCF-7 and MDA-MB-231 human breast cancer cells.…”