A ligand for the aryl hydrocarbon receptor isolated from lung.
The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is best known because it mediates the actions of polycyclic and halogenated aromatic hydrocarbon environmental toxicants such as 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. We report here the successful identification of an endogenous ligand for this receptor; approximately 20 microg was isolated in pure form from 35 kg of porcine lung. Its structure was deduced as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester from extensive physical measurements and quantum mechanical calculations. In a reporter gene assay, this ligand activates the AHR with a potency five times greater than that of beta-naphthoflavone, a prototypical synthetic AHR ligand. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester competes with 2,3,7,8-[(3)H]tetrachlorodibenzo-p-dioxin for binding to human, murine, and fish AHRs, thus showing that AHR activation is caused by direct receptor binding, and that recognition of this endogenous ligand is conserved from early vertebrates (fish) to humans.
Song
Jiasheng
J
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, Madison 53706, USA.
Clagett-Dame
Margaret
M
Peterson
Richard E
RE
Hahn
Mark E
ME
Westler
William M
WM
Sicinski
Rafal R
RR
DeLuca
Hector F
HF
D000818:Animals; D002478:Cells, Cultured; D017930:Genes, Reporter; D007211:Indoles; D007700:Kinetics; D008024:Ligands; D008168:Lung / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D011789:Quantum Theory; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared; D013844:Thiazoles
C548651:2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester; D007211:Indoles; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D013844:Thiazoles