TLR2 controls intestinal carcinogen detoxication by CYP1A1

• Published in: PloS one Vol. 7; no. 3; p. e32309
• Main Authors: Do, Khoa Nguyen, Fink, Lisbeth Nielsen, Jensen, Thomas Elbenhardt, Gautier, Laurent, Parlesak, Alexandr
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.03.2012; Public Library of Science (PLoS)
• Subjects: Animals; Antigens; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Bacteria; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Benzo(a)pyrene; Benzo(a)pyrene - pharmacokinetics; Benzo(a)pyrene - pharmacology; Benzopyrene; Biology; Cancer; Carcinogens; Carcinogens - pharmacokinetics; Carcinogens - pharmacology; Cell walls; Colon; Colonic Polyps - enzymology; Colonic Polyps - genetics; Colonic Polyps - pathology; CYP1A2 protein; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P450; Cytokines; Deoxyribonucleic acid; Dioxins; DNA; Enterocytes; Experiments; Gastric cancer; Gene expression; Genotypes; Humans; Hydrocarbons; Immune system; Inactivation, Metabolic - genetics; Inflammation; Inflammatory response; Intestinal microflora; Intestine; Intestines - enzymology; Intestines - microbiology; Kinases; Liver - enzymology; Localization; Medicine; Metabolism; Mice; Mice, Knockout; Microbiota; Microbiota (Symbiotic organisms); Organ Specificity; Polycyclic aromatic hydrocarbons; Polyps; Proteins; Pyrene; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Rodents; Stomach cancer; TLR2 protein; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0032309

Intestinal cytochrome P450 subclass 1A1 (CYP1A1) contributes to a metabolic "shield" protecting the host from ingested carcinogens such as polycyclic aromatic hydrocarbons (PAH). The expression of CYP1 (including CYP1A2 and CYP1B1) is considered to depend solely on a heterodimeric transcription factor consisting of the arylhydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT). So far, no interference has been noted between the regulation of CYP1 and the activation of Toll-like receptor 2 (TLR2), which modulates the inflammatory response to bacterial cell wall components in immune cells and enterocytes. Here we report that intestinal CYP1A1 is silenced in TLR2-deficient mice, even when under exposure to the carcinogenic PAH benzo[a]pyrene (BaP). In contrast, hepatic CYP1A1 was moderately induced in TLR2-deficient mice without restoring their ability to clear BaP from systemic circulation, as present in wild-type animals. After feeding of BaP for 21 days, only TLR2(-/-) mice, but not their wild type littermates developed polyps in the colon. Gene expressions and protein concentrations of AHR and ARNT in the intestine did not differ between the genotypes. In conclusion, the presence of ligands for TLR2 of bacterial origin seems to be crucial for detoxication of luminal carcinogens by CYP1A1 in the intestine. This unprecedented finding indicates a complex interplay between the immune system of the host and intestinal bacteria with detoxication mechanisms. This highlights the relevance of intestinal microbiota when trying to unravel pathways present in mammals and opens new perspectives for research in human health.