title: TLR2 controls intestinal carcinogen detoxication by CYP1A1.
abstract: 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.
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark (DTU), Lyngby, Denmark.
authors.forename: Khoa Nguyen
authors.initials: KN
authors.lastname: Do
authors.forename: Lisbeth Nielsen
authors.initials: LN
authors.lastname: Fink
authors.forename: Thomas Elbenhardt
authors.initials: TE
authors.lastname: Jensen
authors.forename: Laurent
authors.initials: L
authors.lastname: Gautier
authors.forename: Alexandr
authors.initials: A
authors.lastname: Parlesak
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics* / Q000494:pharmacology; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000494:pharmacology; D003111:Colonic Polyps / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007422:Intestines / Q000201:enzymology* / Q000382:microbiology; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D018336:Receptors, Aryl Hydrocarbon; D051195:Toll-Like Receptor 2; C111235:AHR protein, human; C497396:ARNT protein, human; C484722:Ahr protein, mouse; C497397:Arnt protein, mouse; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; C569463:CYP1A1 protein, human