Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR

Abstract Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We...

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Autores principales:	Christopher Manzella, Megha Singhal, Waddah A. Alrefai, Seema Saksena, Pradeep K. Dudeja, Ravinder K. Gill
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/519824b2f4d143929624a61385e070f6
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spelling	oai:doaj.org-article:519824b2f4d143929624a61385e070f62021-12-02T15:07:56ZSerotonin is an endogenous regulator of intestinal CYP1A1 via AhR10.1038/s41598-018-24213-52045-2322https://doaj.org/article/519824b2f4d143929624a61385e070f62018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-24213-5https://doaj.org/toc/2045-2322Abstract Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We tested the hypothesis that serotonin (5-HT) is an endogenous activator of AhR in intestinal epithelial cells. Treatment of Caco-2 monolayers with 5-HT induced CYP1A1 mRNA in a time- and concentration-dependent manner and also stimulated CYP1A1 activity. CYP1A1 induction by 5-HT was dependent upon uptake via serotonin transporter (SERT). Antagonism of AhR and knockdown of AhR and its binding partner aryl hydrocarbon receptor nuclear translocator (ARNT) attenuated CYP1A1 induction by 5-HT. Activation of AhR was evident by its nuclear translocation after 5-HT treatment and by induction of an AhR-responsive luciferase reporter. In vivo studies showed a dramatic decrease in CYP1A1 expression and other AhR target genes in SERT KO ileal mucosa by microarray analysis. These results suggest that intracellular accumulation of 5-HT via SERT induces CYP1A1 expression via AhR in intestinal epithelial cells, and SERT deficiency in vivo impairs activation of AhR. Our studies provide a novel link between the serotonergic and AhR pathways which has implications in xenobiotic metabolism and intestinal inflammation.Christopher ManzellaMegha SinghalWaddah A. AlrefaiSeema SaksenaPradeep K. DudejaRavinder K. GillNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christopher Manzella Megha Singhal Waddah A. Alrefai Seema Saksena Pradeep K. Dudeja Ravinder K. Gill Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR
description	Abstract Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We tested the hypothesis that serotonin (5-HT) is an endogenous activator of AhR in intestinal epithelial cells. Treatment of Caco-2 monolayers with 5-HT induced CYP1A1 mRNA in a time- and concentration-dependent manner and also stimulated CYP1A1 activity. CYP1A1 induction by 5-HT was dependent upon uptake via serotonin transporter (SERT). Antagonism of AhR and knockdown of AhR and its binding partner aryl hydrocarbon receptor nuclear translocator (ARNT) attenuated CYP1A1 induction by 5-HT. Activation of AhR was evident by its nuclear translocation after 5-HT treatment and by induction of an AhR-responsive luciferase reporter. In vivo studies showed a dramatic decrease in CYP1A1 expression and other AhR target genes in SERT KO ileal mucosa by microarray analysis. These results suggest that intracellular accumulation of 5-HT via SERT induces CYP1A1 expression via AhR in intestinal epithelial cells, and SERT deficiency in vivo impairs activation of AhR. Our studies provide a novel link between the serotonergic and AhR pathways which has implications in xenobiotic metabolism and intestinal inflammation.
format	article
author	Christopher Manzella Megha Singhal Waddah A. Alrefai Seema Saksena Pradeep K. Dudeja Ravinder K. Gill
author_facet	Christopher Manzella Megha Singhal Waddah A. Alrefai Seema Saksena Pradeep K. Dudeja Ravinder K. Gill
author_sort	Christopher Manzella
title	Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR
title_short	Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR
title_full	Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR
title_fullStr	Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR
title_full_unstemmed	Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR
title_sort	serotonin is an endogenous regulator of intestinal cyp1a1 via ahr
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/519824b2f4d143929624a61385e070f6
work_keys_str_mv	AT christophermanzella serotoninisanendogenousregulatorofintestinalcyp1a1viaahr AT meghasinghal serotoninisanendogenousregulatorofintestinalcyp1a1viaahr AT waddahaalrefai serotoninisanendogenousregulatorofintestinalcyp1a1viaahr AT seemasaksena serotoninisanendogenousregulatorofintestinalcyp1a1viaahr AT pradeepkdudeja serotoninisanendogenousregulatorofintestinalcyp1a1viaahr AT ravinderkgill serotoninisanendogenousregulatorofintestinalcyp1a1viaahr
_version_	1718388315272511488

Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR

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