PUBLICATION
Naturally Occurring Marine Brominated Indoles Are Aryl Hydrocarbon Receptor Ligands/Agonists
- Authors
- DeGroot, D.E., Franks, D.G., Higa, T., Tanaka, J., Hahn, M.E., Denison, M.S.
- ID
- ZDB-PUB-150603-9
- Date
- 2015
- Source
- Chemical Research in Toxicology 28(6): 1176-85 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- RNA, Messenger/metabolism
- Guinea Pigs
- Indoles/chemistry*
- Indoles/isolation & purification
- Indoles/pharmacology*
- Zebrafish
- Cells, Cultured
- Molecular Structure
- Biological Products/chemistry*
- Biological Products/isolation & purification
- Biological Products/pharmacology*
- Laurencia/chemistry
- Structure-Activity Relationship
- Receptors, Aryl Hydrocarbon/agonists*
- Receptors, Aryl Hydrocarbon/metabolism*
- Humans
- Animals
- Cytochrome P-450 CYP1A1/metabolism
- Ligands
- Hep G2 Cells
- PubMed
- 26001051 Full text @ Chem. Res. Toxicol.
- CTD
- 26001051
Citation
DeGroot, D.E., Franks, D.G., Higa, T., Tanaka, J., Hahn, M.E., Denison, M.S. (2015) Naturally Occurring Marine Brominated Indoles Are Aryl Hydrocarbon Receptor Ligands/Agonists. Chemical Research in Toxicology. 28(6):1176-85.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping