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- Bergander, L, et al.
(author)
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Characterization of in vitro metabolites of the aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b] carbazole by liquid chromatography-mass spectrometry and NMR.
- 2003
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In: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 31:2, s. 233-241
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Journal article (peer-reviewed)abstract
- The tryptophan photoproduct 6-formylindolo[3,2-b] carbazole (FICZ) exhibits the highest aryl hydrocarbon receptor (AhR) binding affinity reported so far. In different cells, in vitro, both extracts of UV-irradiated tryptophan and the synthesized pure compound FICZ induce a rapid and transient expression of AhR-regulated genes. The transient induction suggests that the biotransformation gene battery induced by AhR activation takes part in a metabolic degradation of the ligand, whereby a low steady-state level is regained. The down-regulation of AhR-regulated gene expression was previously shown to be dependent on cytochrome P450 1A1 (CYP1A1). Metabolism of FICZ generates five major metabolites, which appeared as three peaks (M1-M3) in the high performance liquid chromatography. The aim of the present study was to use rat liver S9 from Aroclor-pretreated rats to produce large enough quantities of FICZ metabolites for structure characterization and to determine their product precursor relationship. NMR analysis of large combined fractions of the metabolites indicated that M3 and M2 contained 2 isomers, respectively. By means of liquid chromatography-mass spectrometry (negative ion electrospray mode) and NMR spectroscopy (by H-1-NMR, correlation spectroscopy, and nuclear Overhauser effect spectroscopy techniques) five metabolites of FICZ were identified, and their structures were elucidated. The molecular weights of the two M3 isomers were 300 and both M2 and M1 compounds demonstrated molecular weights of 316, corresponding to addition of one (M3) and of two oxygen (M2 and M1), respectively. The structures were assigned as 2- and 8-hydroxy (M3), 2,10- and 4,8-dihydroxy (M2) and 2,8-dihydroxy derivatives of indolo[3,2-b] carbazole-6-carboxaldehyde (6-formylindolo[ 3,2-b] carbazole).
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- Luecke, S., et al.
(author)
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Cytochrome P450 1A1 gene regulation by UVB involves crosstalk between the aryl hydrocarbon receptor and nuclear factor kappa B
- 2010
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In: Chemico-Biological Interactions. - : Elsevier BV. - 0009-2797 .- 1872-7786. ; 184:3, s. 466-473
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Journal article (peer-reviewed)abstract
- UVB induces the expression of genes controlled by the aryl hydrocarbon receptor (AhR). a transcription factor that has been implicated in the UV stress response. In this study, we used the human hepatoma cell line HepG2 to investigate in more detail the effects of UVB irradiation on AhR activation and induction of cytochrome P450 1A1 (CYP1A1), a highly AhR-responsive gene. The CYP1A1 enzyme efficiently degrades 6-formylindolo[3,2-b]carbazole (FICZ), a high affinity ligand and suggested endogenous activator of the AhR. We show that physiologically relevant doses of UVB suppress CYP1A1 gene expression immediately after irradiation, but induce its expression later in an AhR-dependent manner. The initial repression phase of CYP1A1 transcription was mediated by another UVB-inducible transcription factor, the nuclear factor kappa B (NF kappa B). Crosstalk between AhR and NF kappa B signaling has earlier been implicated to control CYP1A1 expression following stimulation by xenobiotics and cytokines. Now, our findings clearly indicate a role of NF kappa B also in UVB-dependent AhR signaling. We also observed that UVB reduced the catalytic activity of the CYP1A1 enzyme. Thereby. UVB attenuated the clearance of FICZ, which led to prolonged AhR activation. We further noted that repeated irradiation with UVB or H2O2 treatment shifted the cells into a refractory state in which AhR signaling could not be efficiently activated by UVB or H2O2, but by ligands. Together, our results suggest that the NF kappa B-mediated initial suppression of CYP1A1 as well as the unresponsiveness of AhR signaling to repeated irradiation may be part of a protective cellular UV stress response.
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