Induction of AHR Signaling in Response to the Indolimine Class of Microbial Stress Metabolites.

Autor: Patel D; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA., Murray IA; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA., Dong F; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA., Annalora AJ; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA., Gowda K; Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA., Coslo DM; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA., Krzeminski J; Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA., Koo I; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA., Hao F; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA., Amin SG; Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA., Marcus CB; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA., Patterson AD; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA., Perdew GH; Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA.
Jazyk: angličtina
Zdroj: Metabolites [Metabolites] 2023 Aug 31; Vol. 13 (9). Date of Electronic Publication: 2023 Aug 31.
DOI: 10.3390/metabo13090985
Abstrakt: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that plays an important role in gastrointestinal barrier function, tumorigenesis, and is an emerging drug target. The resident microbiota is capable of metabolizing tryptophan to metabolites that are AHR ligands (e.g., indole-3-acetate). Recently, a novel set of mutagenic tryptophan metabolites named indolimines have been identified that are produced by M. morganii in the gastrointestinal tract. Here, we determined that indolimine-200, -214, and -248 are direct AHR ligands that can induce Cyp1a1 transcription and subsequent CYP1A1 enzymatic activity capable of metabolizing the carcinogen benzo(a)pyrene in microsomal assays. In addition, indolimines enhance IL6 expression in a colonic tumor cell line in combination with cytokine treatment. The concentration of indolimine-248 that induces AHR transcriptional activity failed to increase DNA damage. These observations reveal an additional aspect of how indolimines may alter colonic tumorigenesis beyond mutagenic activity.
Databáze: MEDLINE