title: Human pregnane X receptor agonism by Ginkgo biloba extract: assessment of the role of individual ginkgolides.
abstract: Ginkgo biloba extract activates pregnane X receptor (PXR), but how this occurs is not known. Therefore, we investigated the mechanism of PXR activation by the extract and the role of five individual terpene trilactones in the activation. In a cell-based reporter gene assay, G. biloba extract activated human PXR (hPXR), and at a concentration present in the extract, ginkgolide A, but not ginkgolide B, ginkgolide C, ginkgolide J, or bilobalide was partially responsible for the increase in hPXR activity of the extract. Likewise, in cultured human hepatocytes, only ginkgolide A contributed to the increase in hPXR target gene expression (CYP3A4 mRNA and CYP3A-mediated testosterone 6β-hydroxylation). The extract, but none of the terpene trilactones, bound to hPXR ligand-binding domain, as analyzed by a time-resolved fluorescence resonance energy transfer competitive binding assay. Only the extract and ginkgolide A recruited steroid receptor coactivator-1, as determined by a mammalian two-hybrid assay. Compared with hPXR, rat PXR (rPXR) was activated to a lesser extent by G. biloba extract. Similar to hPXR, only ginkgolide A contributed to rPXR activation by the extract. In contrast to the effect of G. biloba extract on PXR function, it did not affect hPXR expression. Overall, the main conclusions are that G. biloba extract is an hPXR agonist, and among the five terpene trilactones investigated, only ginkgolide A contributes to the actions of the extract. Our findings provide insights into the biological and chemical mechanisms of hPXR activation by G. biloba extract.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Aik Jiang
authors.initials: AJ
authors.lastname: Lau
authors.forename: Guixiang
authors.initials: G
authors.lastname: Yang
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rajaraman
authors.forename: Christie C
authors.initials: CC
authors.lastname: Baucom
authors.forename: Thomas K H
authors.initials: TK
authors.lastname: Chang
mesh_terms: D000368:Aged; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D020441:Ginkgo biloba / Q000737:chemistry*; D046934:Ginkgolides / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000378:metabolism / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014162:Transfection
chemical_list: D046934:Ginkgolides; D007783:Lactones; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011285:Pregnenolone Carbonitrile; D013739:Testosterone; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; C477042:ginkgolide A; D012293:Rifampin