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.
References
[1]
Jin MS, Lee JO (2008) Structures of the toll-like receptor family and its ligand complexes. Immunity 29: 182–191.
[2]
Barton GM, Kagan JC (2009) A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9: 535–542.
[3]
Uematsu S, Akira S (2008) Toll-like receptors (TLRs) and their ligands. Handb Exp Pharmacol 183: 1–20.
[4]
Kawai T, Akira S (2006) Innate immune recognition of viral infection. Nat Immunol 7: 131–137.
[5]
O'Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7: 353–364.
[6]
Mele T, Madrenas J (2010) TLR2 signalling: At the crossroads of commensalism, invasive infections and toxic shock syndrome by Staphylococcus aureus. Int J Biochem Cell Biol 42: 1066–1071.
[7]
Rafter J (2004) The effects of probiotics on colon cancer development. Nutr Res Rev 17: 277–284.
[8]
Waldman JM, Lioy PJ, Greenberg A, Butler JP (1991) Analysis of human exposure to benzo(a)pyrene via inhalation and food ingestion in the Total Human Environmental Exposure Study (THEES). J Expo Anal Environ Epidemiol 1: 193–225.
[9]
Alexandrov K, Rojas M, Satarug S (2010) The critical DNA damage by benzo(a)pyrene in lung tissues of smokers and approaches to preventing its formation. Toxicol Lett 198: 63–68.
[10]
Gu J, Horikawa Y, Chen M, Dinney CP, Wu X (2008) Benzo(a)pyrene diol epoxide-induced chromosome 9p21 aberrations are associated with increased risk of bladder cancer. Cancer Epidemiol Biomarkers Prev 17: 2445–2450.
[11]
Nebert DW, Dalton TP, Okey AB, Gonzalez FJ (2004) Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 279: 23847–23850.
[12]
Chiaro CR, Patel RD, Marcus CB, Perdew GH (2007) Evidence for an aryl hydrocarbon receptor-mediated cytochrome p450 autoregulatory pathway. Mol Pharmacol 72: 1369–1379.
[13]
Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, et al. (2000) Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 59: 65–85.
[14]
Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, et al. (2002) Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J Immunol 168: 348–355.
[15]
Uno S, Dalton TP, Dragin N, Curran CP, Derkenne S, et al. (2006) Oral benzo[a]pyrene in Cyp1 knockout mouse lines: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body burden and clearance rate. Mol Pharmacol 69: 1103–1114.
[16]
Hruz T, Laule O, Szabo G, Wessendorp F, Bleuler S, et al. (2008) Genevestigator v3: a reference expression database for the meta-analysis of transcriptomes. Adv Bioinformatics 420747.
[17]
Uno S, Dalton TP, Derkenne S, Curran CP, Miller ML, et al. (2004) Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. Mol Pharmacol 65: 1225–1237.
[18]
Wagnerberger S, Sch？fer C, Bode C, Parlesak A (2006) Saturation of retinol-binding protein correlates closely to the severity of alcohol-induced liver disease. Alcohol 38: 37–43.
[19]
Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W, editors. Bioinformatics and Computational Biology Solutions using R and Bioconductor. Springer, New York. pp. 397–420.
[20]
Wattenberg LW, Leong JL, Strand PJ (1962) Benzpyrene hydroxylase activity in the gastrointestinal tract. Cancer Res 22: 1120–1125.
[21]
Uno S, Dragin N, Miller ML, Dalton TP, Gonzalez FJ, et al. (2008) Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract. Free Radic Biol Med 44: 570–583.
[22]
Traber PG, McDonnell WM, Wang W, Florence R (1992) Expression and regulation of cytochrome P-450 I genes (CYP1A1 and CYP1A2) in the rat alimentary tract. Biochim Biophys Acta 1171: 167–175.
[23]
Zhang QY, Wikoff J, Dunbar D, Fasco M, Kaminsky L (1997) Regulation of cytochrome P4501A1 expression in rat small intestine. Drug Metab Dispos 25: 21–26.
[24]
Lindeskog P, Overvik E, Nilsson L, Nord CE, Gustafsson JA (1988) Influence of fried meat and fiber on cytochrome P-450 mediated activity and excretion of mutagens in rats. Mutat Res 204: 553–563.
[25]
Fontana RJ, Lown KS, Paine MF, Fortlage L, Santella RM, et al. (1999) Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers. Gastroenterology 117: 89–98.
[26]
Ito S, Chen C, Satoh J, Yim S, Gonzalez FJ (2007) Dietary phytochemicals regulate whole-body CYP1A1 expression through an aryl hydrocarbonreceptor nuclear translocator-dependent system in gut. J Clin Invest 117: 1940–1950.
[27]
Guengerich FP (2000) Metabolism of chemical carcinogens. Carcinogenesis 21: 345–351.
[28]
Burk O, Koch I, Raucy J, Hustert E, Eichelbaum M, et al. (2004) The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J Biol Chem 279: 38379–38385.
[29]
Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF (1989) Human P450PA (P450-1A2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic amines. Proc Natl Acad Sci USA 86: 7696–7700.
[30]
Grover PL, Sims P (1968) Enzyme-catalysed reactions of polycyclic hydrocarbons with deoxyribonucleic acid and protein in vitro. Biochem J 110: 159–160.
[31]
Nebert DW (1989) The Ah locus: genetic differences in toxicity, cancer, mutation, and birth defects. Crit Rev Toxicol 20: 153–174.
[32]
Conney AH (2003) Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the Seventh DeWitt S. Goodman Lecture. Cancer Res 63: 7005–7031.
[33]
Bergheim I, Bode C, Parlesak A (2005) Decreased expression of cytochrome P450 protein in non-malignant colonic tissue of patients with colonic adenoma. BMC Gastroenterol 5: 34.
[34]
Shi Z, Dragin N, Gálvez-Peralta M, Jorge-Nebert LF, Miller ML, et al. (2010) Organ-specific roles of CYP1A1 during detoxication of dietary benzo[a]pyrene. Mol Pharmacol 78: 46–57.
[35]
Lowe EL, Crother TR, Rabizadeh S, Hu B, Wang H, et al. (2010) Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS One 5: e13027.
[36]
Ozaki A, Morishita Y, Oowada T, Itagaki S, Mizutani T (1998) Inhibition of polyposis in the small intestine of BALB/c mice by intestinal bacteria. Cancer Lett 131: 153–156.
[37]
Z？hringer U, Lindner B, Inamura S, Heine H, Alexander C (2008) TLR2 - promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. Immunobiology 213: 205–224.
[38]
Tahara T, Arisawa T, Wang F, Shibata T, Nakamura M, et al. (2007) Toll-like receptor 2 ？196 to 174del polymorphism influences the susceptibility of Japanese people to gastric cancer. Cancer Sci 98: 1790–1794.
[39]
Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M (2009) Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31: 321–330.
[40]
Sanchez Y, Rosado Jde D, Vega L, Elizondo G, Estrada-Mu？iz E, et al. (2010) The unexpected role for the aryl hydrocarbon receptor on susceptibility to experimental toxoplasmosis. J Biomed Biotechnol 2010: 505694.
[41]
Poland A, Palen D, Glover E (1994) Analysis of the four alleles of the murine aryl hydrocarbon receptor. Mol Pharmacol 46: 915–921.
[42]
Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, et al. (2006) Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. Mol Pharmacol 69: 140–153.
[43]
Nebert DW, Karp CL (2008) Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology. J Biol Chem 283: 36061–36065.
[44]
Zeldin DC, Foley J, Goldsworthy SM, Cook ME, Boyle JE, et al. (1997) CYP2J subfamily cytochrome P450s in the gastrointestinal tract: expression, localization, and potential functional significance. Mol Pharmacol 51: 931–943.
[45]
Schwarz D, Kisselev P, Ericksen SS, Szklarz GD, Chernogolov A, et al. (2004) Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1: highly stereoselective formation of 17(R),18(S)-epoxyeicosatetraenoic acid. Biochem Pharmacol 67: 1445–1457.
[46]
Node K, Huo Y, Ruan X, Yang B, Spiecker M, et al. (1999) Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285: 1276–1279.
[47]
Miyata N, Roman RJ (2005) Role of 20-hydroxyeicosatetraenoic acid (20-HETE) in vascular system. J Smooth Musc Res 41: 175–193.
