title: 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 [(3)H]TCDD for binding to the AhR and to stimulate AhR transformation and DNA binding in vitro. Taken together, these results indicate that marine-derived brominated indoles are members of a new class of naturally occurring AhR agonists.
authors.affiliation: †Department of Environmental Toxicology, University of California, Davis, California 95616, United States.
authors.forename: Danica E
authors.initials: DE
authors.lastname: DeGroot
authors.affiliation: ‡Department of Biology and the Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543, United States.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Franks
authors.affiliation: §Department of Chemistry, Biology, and Marine Sciences, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Higa
authors.affiliation: §Department of Chemistry, Biology, and Marine Sciences, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: ‡Department of Biology and the Woods Hole Center for Oceans and Human Health, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hahn
authors.affiliation: †Department of Environmental Toxicology, University of California, Davis, California 95616, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D006168:Guinea Pigs; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D044722:Laurencia / Q000737:chemistry; D008024:Ligands; D015394:Molecular Structure; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: D001688:Biological Products; D007211:Indoles; D008024:Ligands; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1