Serotonin modulates AhR activation by interfering with CYP1A1-mediated clearance of AhR ligands was written by Manzella, Christopher R.;Ackerman, Max;Singhal, Megha;Ticho, Alexander L.;Ceh, Justin;Alrefai, Waddah A.;Saksena, Seema;Dudeja, Pradeep K.;Gill, Ravinder K.. And the article was included in Cellular Physiology & Biochemistry in 2020.Synthetic Route of C19H12N2O This article mentions the following:
Background/Aims: Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and hormone with important physiol. functions in many organs, including the intestine. We have previously shown that 5-HT activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells (IECs) via a serotonin transporter (SERT)-dependent mechanism. AhR is a nuclear receptor that binds a variety of mols. including tryptophan (TRP) metabolites to regulate physiol. processes in the intestine including xenobiotic detoxification and immune modulation. We hypothesized that 5-HT activates AhR indirectly by interfering with metabolic clearance of AhR ligands by cytochrome P 450 1A1 (CYP1A1). Methods: Inhibition of CYP1A1 activity by 5-HT was assessed in the human intestinal epithelial cell line Caco-2 and recombinant CYP1A1 microsomes using both luciferase and LC-MS/MS. Degradation of 5-HT by recombinant CYP1A1 was measured by LC-MS/MS. For in vitro studies, CYP1A1 and CYP1B1 mRNA expression levels were measured by RT-PCR and CYP1A1 activity was measured by ethoxyresorufin-O-deethylase (EROD) assays. For in vivo studies, AhR ligands were administered to SERT KO mice and WT littermates and intestinal mucosa CYP1A1 mRNA was measured. Results: We show that 5-HT inhibits metabolism of both the pro-luciferin CYP1A1 substrate Luc-CEE as well as the high affinity AhR ligand 6-formylindolo[3,2-b] carbazole (FICZ). Recombinant CYP1A1 assays revealed that 5-HT is metabolized by CYP1A1 in an NADPH dependent manner. Treatment with 5-HT in TRP-free medium, which is devoid of trace AhR ligands, showed that 5-HT requires the presence of AhR ligands to activate AhR. Cotreatment with 5-HT and FICZ confirmed that 5-HT potentiates induction of AhR target genes by AhR ligands. However, this was only true for ligands which are CYP1A1 substrates such as FICZ. Administration of 尾-naphthoflavone by gavage or indole-3-carbinol via diet to SERT KO mice revealed that lack of SERT impairs intestinal AhR activation. Conclusion: Our studies provide novel evidence of crosstalk between serotonergic and AhR signaling where 5-HT can influence the ability of AhR ligands to activate the receptor in the intestine. In the experiment, the researchers used many compounds, for example, 5,11-Dihydroindolo[3,2-b]carbazole-6-carbaldehyde (cas: 172922-91-7Synthetic Route of C19H12N2O).
5,11-Dihydroindolo[3,2-b]carbazole-6-carbaldehyde (cas: 172922-91-7) belongs to indole derivatives. Indole is an important structural motif of various drugs, therapeutic leads besides its prevalence in numerous natural products, agrochemicals, perfumery, and dyes.Indole was synthesized in moderate yield via an o-naphthoquinone catalyzed tandem cross-coupling of substituted aniline and benzylamine under aerobic oxidation conditions.Synthetic Route of C19H12N2O
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