title: Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ.
abstract: Activation of the aryl hydrocarbon receptor (AhR), a conserved transcription factor best known as a target for highly toxic halogenated substances such as dioxin, under normal xenobiotic-free conditions is of considerable scientific interest. We have demonstrated previously that a photoproduct of tryptophan, 6-formylindolo[3,2-b]carbazole (FICZ), fulfills the criteria for an endogenous ligand for this receptor and proposed that this compound is the enigmatic mediator of the physiological functions of AhR. Here, we describe novel light-independent pathways by which FICZ can be formed. The oxidant H2O2 was shown to convert tryptophan to FICZ on its own in the absence of light. The enzymatic deamination of tryptamine yielded indole-3-acetaldehyde (I3A), which then rearranged to FICZ and its oxidation product, indolo[3,2-b]carbazole-6-carboxylic acid (CICZ). Indole-3-pyruvate (I3P) also produced I3A, FICZ, and CICZ. Malassezia yeast species, which constitute a part of the normal skin microbiota, produce a number of AhR activators from tryptophan. We identified both FICZ and CICZ among those products. Formation of FICZ from tryptophan or I3P produces a complex mixture of indole derivatives, some of which are CYP1A1 inhibitors. These can hinder the cellular clearance of FICZ and thereby increase its power as an AhR agonist. We present a general molecular mechanism involving dehydrogenations and oxidative coupling for the formation of FICZ in which I3A is the important precursor. In conclusion, our results suggest that FICZ is likely to be formed systemically.
authors.forename: Anna
authors.initials: A
authors.lastname: Smirnova
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet , SE-171 77 Stockholm, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Wincent
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet , SE-171 77 Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Vikström Bergander
authors.forename: Tomas
authors.initials: T
authors.lastname: Alsberg
authors.affiliation: Department of Biosciences at Novum, Karolinska Institutet , SE-141 57 Huddinge, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Bergman
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet , SE-171 77 Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Rannug
authors.forename: Ulf
authors.initials: U
authors.lastname: Rannug
mesh_terms: D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008027:Light; D015394:Molecular Structure; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D004791:Enzyme Inhibitors; D018336:Receptors, Aryl Hydrocarbon; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1