The Suggested Physiologic Aryl Hydrocarbon Receptor Activator and Cytochrome P4501 Substrate 6-Formylindolo[3,2-b]carbazole Is Present in Humans Export

@article{citeulike:4193727, abstract = {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. 10.1074/jbc.M808321200}, author = {Wincent, Emma and Amini, Nahid and Luecke, Sandra and Glatt, Hansruedi and Bergman, Jan and Crescenzi, Carlo and Rannug, Agneta and Rannug, Ulf}, citeulike-article-id = {4193727}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M808321200}, citeulike-linkout-1 = {http://www.jbc.org/cgi/content/abstract/284/5/2690}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19054769}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19054769}, day = {30}, doi = {10.1074/jbc.M808321200}, journal = {J. Biol. Chem.}, keywords = {aryl-hc, cytochrome, urgent, web-study}, month = {January}, number = {5}, pages = {2690--2696}, posted-at = {2009-03-19 01:48:16}, priority = {2}, title = {The Suggested Physiologic Aryl Hydrocarbon Receptor Activator and Cytochrome P4501 Substrate 6-Formylindolo[3,2-b]carbazole Is Present in Humans}, url = {http://dx.doi.org/10.1074/jbc.M808321200}, volume = {284}, year = {2009} }

TY - JOUR ID - citeulike:4193727 L3 - citeulike-article-id:4193727 N2 - 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. 10.1074/jbc.M808321200 IS - 5 JF - J. Biol. Chem. EP - 2696 TI - The Suggested Physiologic Aryl Hydrocarbon Receptor Activator and Cytochrome P4501 Substrate 6-Formylindolo[3,2-b]carbazole Is Present in Humans VL - 284 SP - 2690 KW - aryl-hc KW - cytochrome KW - urgent KW - web-study AU - Wincent, Emma AU - Amini, Nahid AU - Luecke, Sandra AU - Glatt, Hansruedi AU - Bergman, Jan AU - Crescenzi, Carlo AU - Rannug, Agneta AU - Rannug, Ulf PY - 2009/01/30/ UR - http://dx.doi.org/10.1074/jbc.M808321200 ER -