Rapid and transient induction of CYP1A1 gene expression in human cells by the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole

Chem Biol Interact. 1998 Mar 12;110(1-2):39-55. doi: 10.1016/s0009-2797(97)00111-7.


Studies to assess the induction of CYP1A1 gene expression by tryptophan derived oxidation products which are suggested as endogenous ligands for the Ah receptor are described. For the two high affinity Ah receptor ligands produced from tryptophan, the chemical structure was recently identified as 6-formylindolo[3,2-b]carbazole (FICZ) and 6,12-diformylindolo[3,2-b]carbazole (dFICZ), respectively. Therefore these two compounds show a close similarity to the indolecarbinol-derived condensation product indolo[3,2-b]carbazole (ICZ). Incubation of cells from a human keratinocyte (HaCaT) cell line together with ICZ, FICZ, dFICZ and some structurally related indole compounds was performed. The compound with the highest affinity to the Ah receptor, FICZ, was found to be the most efficient inducer of CYP1A1 gene expression in short time incubation (0.5 h) experiments. With longer incubation times (24 h) ICZ was the most efficient inducer. The two most active compounds, FICZ and ICZ, caused increased mRNA levels already at a concentration of 100 pM. FICZ was also shown to increase CYP1A1 mRNA levels in fresh human peripheral blood cells at the same low concentration. FICZ and ICZ were furthermore compared with regard to their capacity to inhibit cDNA-expressed human CYP1A1 enzyme and FICZ was found to be the most potent inhibitor. The inhibition was, however, transient in character indicating that FICZ is also an exceptionally good substrate for the CYP1A1 enzyme. The results showing the potent and transient effect of these formylindolocarbazoles, thus emphasize their important properties as signal substances in the Ah receptor pathway. This makes the most potent compound, FICZ, a good candidate for the endogenous ligand of the Ah receptor necessary for normal development and for the basal expression of Ah receptor-dependent genes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carbazoles / pharmacology*
  • Cells, Cultured
  • Cytochrome P-450 CYP1A1 / antagonists & inhibitors
  • Cytochrome P-450 CYP1A1 / biosynthesis*
  • Cytochrome P-450 CYP1A1 / genetics
  • DNA, Single-Stranded / biosynthesis
  • Dose-Response Relationship, Drug
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression
  • Humans
  • Indoles / pharmacology*
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Ligands
  • Molecular Sequence Data
  • Photochemistry
  • RNA, Messenger / biosynthesis
  • Receptors, Aryl Hydrocarbon / drug effects
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Time Factors
  • Tryptophan / chemistry


  • 6,12-diformylindolo(3,2-b)carbazole
  • 6-formylindolo(3,2-b)carbazole
  • Carbazoles
  • DNA, Single-Stranded
  • Enzyme Inhibitors
  • Indoles
  • Ligands
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Tryptophan
  • Cytochrome P-450 CYP1A1