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The Suggested Physiologic Aryl Hydrocarbon ReceptorActivator and Cytochrome P4501 Substrate6-Formylindolo[3,2-b]carbazole Is Present in Humans
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Analytical Chemistry.
Institute for Environmental Medicine, Karolinska Institute.
German Institute of Human Nutrition Potsdam-Rehbruecke.
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2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 5, 2690-2696 p.Article in journal (Refereed) Published
Abstract [en]

Dioxins and other polycyclic aromatic compounds formedduring the combustion of waste and fossil fuels represent a riskto human health, as well as to the well being of our environment.Compounds of this nature exert carcinogenic and endocrinedisruptingeffects in experimental animals by binding to theorphan aryl hydrocarbon receptor (AhR). Understanding themechanism of action of these pollutants, as well as the physiologicalrole(s) of the AhR, requires identification of the endogenousligand(s) of this receptor. We reported earlier that activationof AhR by ultraviolet radiation is mediated by thechromophoric amino acid tryptophan (Trp), and we suggestedthat a new class of compounds derived from Trp, in particular6-formylindolo[3,2-b]carbazole (FICZ), acts as natural highaffinity ligands for this receptor. Here we describe seven newFICZ-derived indolo[3,2-b]carbazole-6-carboxylic acid metabolitesand two sulfoconjugates, and we demonstrate the following.(i) FICZ is formed efficiently by photolysis of Trp uponexposure to visible light. (ii) FICZ is an exceptionally good substratefor cytochromes P450 (CYP) 1A1, 1A2, and 1B1, and itshydroxylated metabolites are remarkably good substrates forthe sulfotransferases (SULTs) 1A1, 1A2, 1B1, and 1E1. Finally,(iii) sulfoconjugates of phenolic metabolites of FICZ are presentin human urine. Our findings indicate that formylindolo[3,2-b]carbazols are the most potent naturally occurring activators ofthe AhR signaling pathway and may be the key substrates of theCYP1 and SULT1 families of enzymes. These conclusions contradictthe widespread view that xenobiotic compounds are themajor AhR ligands and CYP1 substrates.

Place, publisher, year, edition, pages
2009. Vol. 284, no 5, 2690-2696 p.
URN: urn:nbn:se:su:diva-37691OAI: diva2:304756
Available from: 2011-01-19 Created: 2010-03-19 Last updated: 2011-01-19Bibliographically approved

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