title: Discovery and biological characterization of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole as an aryl hydrocarbon receptor activator generated by photoactivation of tryptophan by sunlight.
abstract: Activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is required for AHR dependent transcriptional activation and TCDD toxicity. We previously reported that aqueous tryptophan exposed to sunlight through window glass (aTRP) contains multiple photoproducts, including the well characterized 6-formylindolo[3,2-b]carbazole (FICZ), capable of activating the AHR and inducing CYP1A and CYP1A-mediated enzyme activities. We report here the isolation from aTRP and chemical characterization and synthesis of 1-(1H-indol-3-yl)-9H-pyrido[3,4-b]indole (IPI), a compound previously identified as a natural product of marine ascidia and now shown to be a TRP photoproduct with AHR-inducing properties. IPI, FICZ and TCDD produced equieffective induction of CYP1A-mediated 7-ethoxyresorufin deethylase (EROD) activity in chick embryo primary hepatocytes and mammalian Hepa1c1c7 cells. EROD induction by IPI was markedly curtailed in AHR-defective c35 cells, supporting the AHR dependence of the IPI response. Although IPI had a higher EC(50) for EROD induction than FICZ, the much larger amount of IPI than FICZ in aTRP makes IPI a prominent contributor to EROD induction in aTRP. IPI was detected in TRP-containing culture medium under ambient laboratory conditions but not in TRP-free medium, consistent with its production from TRP. Cotreatment of hepatocytes with submaximal EROD-inducing doses of IPI and FICZ or TCDD produced additive increases in EROD without synergistic or inhibitory interactions. IPI and FICZ were readily metabolized by cultured hepatocytes. In addition to increasing CYP1A4 mRNA and EROD, IPI and FICZ decreased hepatocyte phosphoenolpyruvate carboxykinase mRNA expression and glucose output, biological effects associated with TCDD metabolic dysregulation. The findings underscore a role for sunlight in generating AHR-activating bioactive molecules.
authors: Department of Pharmacology, Weill Medical College of Cornell University, NY 10065, USA.
authors: Silvia
authors: S
authors: Diani-Moore
authors: Yuliang
authors: Y
authors: Ma
authors: Erin
authors: E
authors: Labitzke
authors: Hui
authors: H
authors: Tao
authors: J
authors: J
authors: David Warren
authors: Jared
authors: J
authors: Anderson
authors: Qiuying
authors: Q
authors: Chen
authors: Steven S
authors: SS
authors: Gross
authors: Arleen B
authors: AB
authors: Rifkind
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media / Q000737:chemistry / Q000528:radiation effects; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D055668:Photochemical Processes; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D021241:Spectrometry, Mass, Electrospray Ionization; D013472:Sunlight; D014364:Tryptophan / Q000737:chemistry / Q000528:radiation effects*
chemical_list: C561449:1-(1H-indol-3-yl)-9H-pyrido(3,4-b)indole; C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D002243:Carbolines; D003470:Culture Media; D017077:Culture Media, Conditioned; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan; D019363:Cytochrome P-450 CYP1A1; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose