The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans.
Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. Compounds of this nature exert carcinogenic and endocrine-disrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor. We reported earlier that activation of AhR by ultraviolet radiation is mediated by the chromophoric amino acid tryptophan (Trp), and we suggested that a new class of compounds derived from Trp, in particular 6-formylindolo[3,2-b]carbazole (FICZ), acts as natural high affinity ligands for this receptor. Here we describe seven new FICZ-derived indolo[3,2-b]carbazole-6-carboxylic acid metabolites and two sulfoconjugates, and we demonstrate the following. (i) FICZ is formed efficiently by photolysis of Trp upon exposure to visible light. (ii) FICZ is an exceptionally good substrate for cytochromes P450 (CYP) 1A1, 1A2, and 1B1, and its hydroxylated metabolites are remarkably good substrates for the sulfotransferases (SULTs) 1A1, 1A2, 1B1, and 1E1. Finally, (iii) sulfoconjugates of phenolic metabolites of FICZ are present in human urine. Our findings indicate that formylindolo[3,2-b]carbazols are the most potent naturally occurring activators of the AhR signaling pathway and may be the key substrates of the CYP1 and SULT1 families of enzymes. These conclusions contradict the widespread view that xenobiotic compounds are the major AhR ligands and CYP1 substrates.
Wincent
Emma
E
Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden.
Amini
Nahid
N
Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
Luecke
Sandra
S
Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Glatt
Hansruedi
H
Department of Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
Bergman
Jan
J
Department of Biosciences at Novum, Karolinska Institutet, S-141 57 Stockholm, Sweden.
Crescenzi
Carlo
C
Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
Rannug
Agneta
A
Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Rannug
Ulf
U
Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden. Electronic address: Ulf.Rannug@gmt.su.se.
D002227:Carbazoles / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry
C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D004791:Enzyme Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System