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Drug Metabolism and Disposition Fast Forward
First published on August 25, 2008; DOI: 10.1124/dmd.108.023499

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Received for publication July 21, 2008.
Revised August 20, 2008.
Accepted for publication August 21, 2008.

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

Eugene Y. H. Yeung 1, Tatsuya Sueyoshi 2, Masahiko Negishi 2, Thomas K. H. Chang 1*

1 The University of British Columbia 2 National Institute of Environmental Health Sciences, NIH

* Address correspondence to: E-mail: tchang{at}unixg.ubc.ca

Abstract

Pregnane X receptor (PXR; NR1I2) is a ligand-activated transcription factor that plays a role not only in drug metabolism and transport, but also in various other biological processes. Ginkgo biloba is a herbal medicine commonly used to manage memory impairment. Treatment of primary cultures of rat hepatocytes with G. biloba extract increases the mRNA expression of CYP3A23, which is a target gene for rat PXR. The present study was conducted to test the hypothesis that G. biloba extract activates PXR. Treatment of mouse PXR (mPXR) or human PXR (hPXR)-transfected HepG2 cells with G. biloba extract at 200 µg/ml increased mPXR and hPXR activation by 3.2-fold and 9.5-fold, respectively. Dose-response analysis showed a log-linear increase in hPXR activation by the extract over the range of 200-800 µg/ml. To determine whether G. biloba extract induces hPXR target gene expression, cultured LS180 human colon adenocarcinoma cells were treated for 72 h with the extract. G. biloba extract at 200, 400, and 800 µg/ml increased CYP3A4 mRNA expression by 1.7-, 2.4-, and 2.5-fold, respectively. The same concentrations of the extract increased CYP3A5 (1.3 to 3.6-fold) and ABCB1 (2.7 to 6.4-fold) mRNA expression. At concentrations (5 and 10 µM) that did not down-regulate PXR gene expression and were not cytotoxic, L-sulforaphane (a hPXR antagonist) decreased CYP3A4, CYP3A5, and ABCB1 gene expression in cells treated with G. biloba extract. In summary, G. biloba extract activated mPXR and hPXR in a cell-based reporter gene assay and induced CYP3A4, CYP3A5, and ABCB1 gene expression in hPXR-expressing LS180 cells.


Key words: CYP induction, CYP3A, p-glycoprotein, PXR, SXR


This article has been cited by other articles:


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Human CYP3A4 and Murine Cyp3A11 Are Regulated by Equol and Genistein via the Pregnane X Receptor in a Species-Specific Manner
J. Nutr., May 1, 2009; 139(5): 898 - 904.
[Abstract] [Full Text] [PDF]


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