Ginkgo biloba Extracts Induce the Expression of Hepatic Drug-metabolizing Enzymes through Activation of PXR and AhR

Abstract

Ginkgo biloba extract (GBE) is extensively used as an herbal remedy for enhancing mental focus and delaying onset of age-related loss of cognitive function. Potentials of related drug-herbal interaction have been highlighted by recent reporters, which indicated GBE causes enhancement of several P450 expression in rodent animals. However, data pertaining to GBE induction of human metabolism is limited, and the underlying mechanisms are not known. In the present study, we aimed to evaluate the metabolism induction profile of EGB761, ginkgolide A (GA), ginkgolide B (GB), and bilobalide (BB) using human primary hepatocyte cultures. Real-time PCR assay was employed to assess mRNA levels of CYP3A4, CYP2B6, CYP1A2, UGT1A1, and MDR1. To assess the potential for GBE activation of transcription factors, cell-based reporter assays for PXR, CAR, and AhR were conducted in HepG2 cells. Results demonstrated that GA and GB strongly induced CYP3A4 and CYP2B6 in human hepatocytes, and activated PXR but not CAR or AhR; EGB761 and BB only resulted in marginal changes in CYP2B6 expression, without activation of either PXR or CAR. In contrast, EGB761 but not GA or GB activated AhR in reporter assays, indicating EGB761 may contain components other than GA or GB, which mediated the activation of AhR. Current results revealed that GBE induces hepatic expression of CYP3A4 and CYP2B6 through the activation of PXR, and GA/GB is the major component responsible for this induction. EGB761 activation of AhR may through an unknown component other than GA. Human CAR is not involved in GBE mediated CYP inductions.