Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes

• Published in: PloS one 2016-05, Vol.11 (5), p.e0154629-e0154629
• Main Authors: Rasmussen, Martin Krøyer, Balaguer, Patrick, Ekstrand, Bo, Daujat-Chavanieu, Martine, Gerbal-Chaloin, Sabine
• Format: Article
• Language: English
• Subjects: Adult; Aged; Analysis; Aromatic compounds; Bacteria; Biology and Life Sciences; Cancer; Carcinogens; Cigarette smoking; CYP1A2 protein; Cytochrome; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P-450 CYP1B1 - genetics; Cytochrome P450; Cytochrome P450 Family 1 - genetics; Drug Partial Agonism; Enzymes; Female; Fermentation; Food science; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Genes; Genes, Reporter - genetics; Hep G2 Cells; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hogs; Homeostasis; Human health and pathology; Humans; Hydrocarbons; Hépatology and Gastroenterology; Indole; Indoles; Intestine; Laboratories; Life Sciences; Liver; Male; Medical research; Medicine; Medicine and Health Sciences; Metabolism; Metabolites; Middle Aged; Penicillin; Receptors, Aryl Hydrocarbon - agonists; Reporter gene; Risk factors; Rodents; siRNA; Skatole - pharmacology; skatole liver metabolism detoxification CYP; Smoking; TCDD; Toxicology; Tryptophan; Urine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154629

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.