Bilobalide in ginkgo biloba extract is a major substance inducing hepatic CYPs

Abstract

In a search for substances related to the marked induction of hepatic cytochrome P450 (CYP) by ginkgo biloba extract (GBE), mice were given either GBE (1000 mg kg(-1)) or fractions of GBE for 5 days. The content and activity of CYPs were induced markedly by a bilobalide-rich fraction, but not by flavonoid-rich fractions. The level of induction by the bilobalide-rich fraction was almost the same as that induced by the unfractionated GBE, suggesting that bilobalide is largely responsible for the CYPs induction. To confirm these findings, mice were given various doses of bilobalide (10.5, 21 and 42 mg kg(-1)), or GBE (1000 mg kg(-1), containing bilobalide at 42 mg kg(-1)). Treatment with bilobalide induced CYPs markedly and in a dose-dependent manner, and the level of induction was quite similar between bilobalide (42 mg kg(-1)) and GBE. Treatment with GBE and with bilobalide greatly induced pentoxyresorufin O-dealkylase activity. These findings indicate that bilobalide is the major substance in GBE that induces hepatic CYPs.

Identification of Ginkgo biloba as a Novel Activator of Pregnane X Receptor

“…The present study provides the first demonstration that a novel action of G. biloba extract is the activation of mouse and human PXR, as assessed by an in vitro cell-based reporter gene assay. The activation of mouse PXR by G. biloba extract is consistent with the previous finding that the in vivo administration of this herbal medicine to mice increases the hepatic microsomal enzyme activity of CYP3A, which is a PXR target gene product (Umegaki et al, 2007). However, G. biloba extract was more effective in activating human PXR than in activating mouse PXR.…”

“…By comparison, it is not clear whether bilobalide contributes to the activation of PXR by G. biloba extract. The in vivo administration of this compound to mice has been reported to increase hepatic microsomal enzyme activity of a PXR target gene product, CYP3A (Umegaki et al, 2007). However, as shown in primary cultures of rat hepatocytes, bilobalide does not increase CYP3A23 gene expression or its associated testosterone 6 β -hydroxylation activity (Chang et al, 2006).…”

“…As demonstrated in primary cultures of rat hepatocytes, G. biloba extract increases CYP3A2, CYP3A18, and CYP3A23 mRNA levels (Chang et al, 2006). The in vivo administration of G. biloba extract has also been shown to increase CYP3A-mediated testosterone 6 β -hydroxylation activity in mouse hepatic microsomes (Umegaki et al, 2007). Given that PXR controls the transcriptional regulation of CYP3A genes (Kliewer et al, 1998), our hypothesis is that G. biloba extract activates PXR.…”

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

“…These reports demonstrate various effects of GBE on the CYP1A2 expression, including induction, non-effects, and repression(10, 40, 41). Our studies in human hepatocytes showed no induction of CYP1A2 by EGb 761 or its terpenoids.…”

Time-Dependent Induction of Hepatic Cytochrome P450 Enzyme Activity and mRNA Expression by Bilobalide in Rats

“…In our previous study using fractionated GBE samples, induction of the CYPs enzyme was observed in mice administered the terpenoid-rich fraction that is mainly bilobalide (11). To elucidate the GBE-drug interactions more clearly, further characterization of the active substance that induces hepatic CYPs is needed.…”