Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of structurally diverse chemicals. In this study, we examined the ability of a series of ginsenosides extracted from ginseng, a traditional Chinese medicine, to bind to and activate/inhibit the AHR and AHR signal transduction. Utilizing a combination of ligand and DNA binding assays, molecular docking and reporter gene analysis, we demonstrated the ability of selected ginsenosides to directly bind to and activate the guinea pig cytosolic AHR, and to stimulate/inhibit AHR-dependent luciferase gene expression in a recombinant guinea pig cell line. Comparative studies revealed significant species differences in the ability of ginsenosides to stimulate AHR-dependent gene expression in guinea pig, rat, mouse and human cell lines. Not only did selected ginsenosides preferentially activate the AHR from one species and not others, mouse cell line was also significantly less responsive to these chemicals than rat and guinea pig cell lines, but the endogenous gene CYP1A1 could still be inducted in mouse cell line. Overall, the ability of these compounds to stimulate AHR signal transduction demonstrated that these ginsenosides are a new class of naturally occurring AHR agonists.
Highlights
The aryl hydrocarbon receptor (AHR) is a basic helix–loop– helix PAS-containing transcription factor, which activates gene expression in a ligand-dependent manner [1]
Stimulation of AHR transformation and DNA binding by TCDD and ginsenosides in vitro The reporter gene expression results demonstrated the ability of selected ginsengosides to activate AHR-dependent gene expression, but they did not address whether this induction was direct or indirect
We examined the ability of ginsenosides to directly stimulate transformation and DNA binding of guinea pig cytosolic AHR in vitro using gel retardation analysis
Summary
The aryl hydrocarbon receptor (AHR) is a basic helix–loop– helix PAS-containing transcription factor, which activates gene expression in a ligand-dependent manner [1]. A relatively large number of natural and synthetic AHR ligands (agonists and antagonists) whose structures and physicochemical characteristics are dramatically different from that of the prototypical HAH and PAH have been identified and characterized [9,10,11]. While the relative potencies of these diverse ligands in intact cells and animals are typically much lower than that of the HAHs and PAHs, predominantly due to differences in their affinity, intrinsic efficacy, and metabolic stability [8,10,11,12], these results demonstrate that the AHR has an extremely promiscuous ligand binding pocket, and raised questions as to the actual spectrum of chemicals that can bind to and activate the AHR and AHR signaling pathway. We have carried out bioassay screening analysis of a wide variety of natural compounds and extracts with the goal to identify and characterize novel AHR ligands, and extend our understanding of the AHR ligand structural diversity
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