Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-Feedback
The aryl hydrocarbon receptor (AHR) exerts major roles in xenobiotic metabolism, and in immune and barrier tissue homeostasis. How AHR activity is regulated by the availability of endogenous ligands is poorly understood. Potent AHR ligands have been shown to exhibit a negative feedback loop through...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2023-07-01
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| Series: | International Journal of Tryptophan Research |
| Online Access: | https://doi.org/10.1177/11786469231182508 |
| _version_ | 1797785157607882752 |
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| author | Fangcong Dong Andrew J Annalora Iain A Murray Yuan Tian Craig B Marcus Andrew D Patterson Gary H Perdew |
| author_facet | Fangcong Dong Andrew J Annalora Iain A Murray Yuan Tian Craig B Marcus Andrew D Patterson Gary H Perdew |
| author_sort | Fangcong Dong |
| collection | DOAJ |
| description | The aryl hydrocarbon receptor (AHR) exerts major roles in xenobiotic metabolism, and in immune and barrier tissue homeostasis. How AHR activity is regulated by the availability of endogenous ligands is poorly understood. Potent AHR ligands have been shown to exhibit a negative feedback loop through induction of CYP1A1, leading to metabolism of the ligand. Our recent study identified and quantified 6 tryptophan metabolites (eg, indole-3-propionic acid, and indole-3-acetic acid) in mouse and human serum, generated by the host and gut microbiome, that are present in sufficient concentrations to individually activate the AHR. Here, these metabolites are not significantly metabolized by CYP1A1/1B1 in an in vitro metabolism assay. In contrast, CYP1A1/1B metabolizes the potent endogenous AHR ligand 6-formylindolo[3,2b]carbazole. Furthermore, molecular modeling of these 6 AHR activating tryptophan metabolites within the active site of CYP1A1/1B1 reveal metabolically unfavorable docking profiles with regard to orientation with the catalytic heme center. In contrast, docking studies confirmed that 6-formylindolo[3,2b]carbazole would be a potent substrate. The lack of CYP1A1 expression in mice fails to influence serum levels of the tryptophan metabolites examined. In addition, marked induction of CYP1A1 by PCB126 exposure in mice failed to alter the serum concentrations of these tryptophan metabolites. These results suggest that certain circulating tryptophan metabolites are not susceptible to an AHR negative feedback loop and are likely important factors that mediate constitutive but low level systemic human AHR activity. |
| first_indexed | 2024-03-13T00:50:07Z |
| format | Article |
| id | doaj.art-30fb87594bd64645bc87c2297be54d65 |
| institution | Directory Open Access Journal |
| issn | 1178-6469 |
| language | English |
| last_indexed | 2024-03-13T00:50:07Z |
| publishDate | 2023-07-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | International Journal of Tryptophan Research |
| spelling | doaj.art-30fb87594bd64645bc87c2297be54d652023-07-07T18:03:30ZengSAGE PublishingInternational Journal of Tryptophan Research1178-64692023-07-011610.1177/11786469231182508Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-FeedbackFangcong Dong0Andrew J Annalora1Iain A Murray2Yuan Tian3Craig B Marcus4Andrew D Patterson5Gary H Perdew6Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, USADepartment of Environmental and Molecular Toxicology, Oregon State University, Corvallis, USADepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, USADepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, USADepartment of Environmental and Molecular Toxicology, Oregon State University, Corvallis, USADepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, USADepartment of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, USAThe aryl hydrocarbon receptor (AHR) exerts major roles in xenobiotic metabolism, and in immune and barrier tissue homeostasis. How AHR activity is regulated by the availability of endogenous ligands is poorly understood. Potent AHR ligands have been shown to exhibit a negative feedback loop through induction of CYP1A1, leading to metabolism of the ligand. Our recent study identified and quantified 6 tryptophan metabolites (eg, indole-3-propionic acid, and indole-3-acetic acid) in mouse and human serum, generated by the host and gut microbiome, that are present in sufficient concentrations to individually activate the AHR. Here, these metabolites are not significantly metabolized by CYP1A1/1B1 in an in vitro metabolism assay. In contrast, CYP1A1/1B metabolizes the potent endogenous AHR ligand 6-formylindolo[3,2b]carbazole. Furthermore, molecular modeling of these 6 AHR activating tryptophan metabolites within the active site of CYP1A1/1B1 reveal metabolically unfavorable docking profiles with regard to orientation with the catalytic heme center. In contrast, docking studies confirmed that 6-formylindolo[3,2b]carbazole would be a potent substrate. The lack of CYP1A1 expression in mice fails to influence serum levels of the tryptophan metabolites examined. In addition, marked induction of CYP1A1 by PCB126 exposure in mice failed to alter the serum concentrations of these tryptophan metabolites. These results suggest that certain circulating tryptophan metabolites are not susceptible to an AHR negative feedback loop and are likely important factors that mediate constitutive but low level systemic human AHR activity.https://doi.org/10.1177/11786469231182508 |
| spellingShingle | Fangcong Dong Andrew J Annalora Iain A Murray Yuan Tian Craig B Marcus Andrew D Patterson Gary H Perdew Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-Feedback International Journal of Tryptophan Research |
| title | Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-Feedback |
| title_full | Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-Feedback |
| title_fullStr | Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-Feedback |
| title_full_unstemmed | Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-Feedback |
| title_short | Endogenous Tryptophan-Derived Ah Receptor Ligands are Dissociated from CYP1A1/1B1-Dependent Negative-Feedback |
| title_sort | endogenous tryptophan derived ah receptor ligands are dissociated from cyp1a1 1b1 dependent negative feedback |
| url | https://doi.org/10.1177/11786469231182508 |
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