Naturally Occurring Marine Brominated Indoles Are Aryl Hydrocarbon Receptor Ligands/Agonists

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the toxic and biological effects of structurally diverse chemicals, including the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As part of a larger effort to identify the full spectrum of chemicals that can bind to and activate the AhR, we have examined the ability of several naturally-occurring marine-derived brominated indoles and brominated (methylthio)indoles (collectively referred to as “brominated indoles”) to bind to the AhR and stimulate AhR-dependent gene expression. Incubation of mouse, rat and guinea pig recombinant cell lines containing a stably transfected AhR-responsive luciferase reporter gene with eight brominated indoles revealed that all compounds stimulated luciferase reporter gene activity, although some species-specific differences were observed. All compounds induced significantly more luciferase activity when incubated with cells for 4 h as compared to 24 h, demonstrating that these compounds are transient activators of the AhR signaling pathway. Three of the brominated indoles induced CYP1A1 mRNA in human HepG2 cells in vitro and Cyp1a mRNA in zebrafish embryos in vivo. The identification of the brominated indoles as direct ligands and activators/agonists of the AhR was confirmed by their ability to compete with [3H]TCDD for binding to the AhR and to stimulate AhR transformation and DNA binding in vitro. Taken together, these marine-derived brominated indoles are members of a new class of naturally-occurring AhR agonists.

Marine natural products

“…[582][583][584] Studies on eight brominated indoles from Laurencia brongniatii 585 have revealed that some of them constitute a new class of relatively potent naturally occurring aryl hydrocarbon receptor (AhR) agonists. 586…”

Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization

“…The AhR ligands can be both xenobiotics and endogenous compounds [8][9][10]. A variety of indole-based compounds have been documented to act as AhR ligands, including indirubin and indigo [11], bilirubin, biliverdin and hemin [12], diindolylmethane [13] and other di-indole derivatives [14], indole-3-carbinol [15], indoxyl-3-sulfate [16,17], ultraviolet photoproducts of tryptophan [18], including 6-formylindolo [3 ,2-b]carbazole (FICZ) [19], marine brominated indoles [20], and several MICTs (TA, IAA [21], IA [17], IND [22], or 3MI [23,24]). Indoles may act as human AhR-selective agonists, but also as AhR antagonists in a context-specific manner [22,25].…”

mRNA Expression and Biomarker Responses in Perch at a Biomonitoring Site in the Baltic Sea – Possible Influence of Natural Brominated Chemicals

“…In addition to brominated dioxins, brominated indoles, brominated methylindoles and brominated carbazoles could be found. Both halogenated carbazoles and indoles have been indicated to be aryl hydrocarbon receptor agonists and, thus, to have the potential to upregulate CYP1A and EROD activity (DeGroot et al, 2015;Mumbo et al, 2015). In the present study, the concentrations of the brominated indoles were generally higher in the 2014 collected fish than in the 2010 fish.…”