title: Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes.
abstract: Skatole (3-methylindole) is a product of bacterial fermentation of tryptophan in the intestine. A significant amount of skatole can also be inhaled during cigarette smoking. Skatole is a pulmonary toxin that induces the expression of aryl hydrocarbon receptor (AhR) regulated genes, such as cytochrome P450 1A1 (CYP1A1), in human bronchial cells. The liver has a high metabolic capacity for skatole and is the first organ encountered by the absorbed skatole; however, the effect of skatole in the liver is unknown. Therefore, we investigated the impact of skatole on hepatic AhR activity and AhR-regulated gene expression. Using reporter gene assays, we showed that skatole activates AhR and that this is accompanied by an increase of CYP1A1, CYP1A2 and CYP1B1 expression in HepG2-C3 and primary human hepatocytes. Specific AhR antagonists and siRNA-mediated AhR silencing demonstrated that skatole-induced CYP1A1 expression is dependent on AhR activation. The effect of skatole was reduced by blocking intrinsic cytochrome P450 activity and indole-3-carbinole, a known skatole metabolite, was a more potent inducer than skatole. Finally, skatole could reduce TCDD-induced CYP1A1 expression, suggesting that skatole is a partial AhR agonist. In conclusion, our findings suggest that skatole and its metabolites affect liver homeostasis by modulating the AhR pathway.
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, Montpellier, F-34290, France.|Montpellier University, UMR 1183, Montpellier, F-34203, France.|Department of Food Science, Aarhus University, Foulum, Denmark.
authors.forename: Martin Krøyer
authors.identifier: 0000-0002-1889-2874
authors.initials: MK
authors.lastname: Rasmussen
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.affiliation: Department of Food Science, Aarhus University, Foulum, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Ekstrand
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, Montpellier, F-34290, France.|CHU Montpellier, Institute of Regenerative Medicine and Biotherapy, Montpellier, F-34290, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Daujat-Chavanieu
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, Montpellier, F-34290, France.|Montpellier University, UMR 1183, Montpellier, F-34203, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gerbal-Chaloin
mesh_terms: D000328:Adult; D000368:Aged; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics; D000072461:Cytochrome P450 Family 1 / Q000235:genetics*; D054333:Drug Partial Agonism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D012862:Skatole / Q000494:pharmacology*
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D012862:Skatole; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D000072461:Cytochrome P450 Family 1