PMID- 25224404 OWN - NLM STAT- MEDLINE DCOM- 20160916 LR - 20151209 IS - 1432-0738 (Electronic) IS - 0340-5761 (Linking) VI - 89 IP - 12 DP - 2015 Dec TI - Activation of the aryl hydrocarbon receptor by carcinogenic aromatic amines and modulatory effects of their N-acetylated metabolites. PG - 2403-12 LID - 10.1007/s00204-014-1367-7 [doi] AB - Aromatic amines (AAs) are an important class of chemicals which account for 12 % of known carcinogens. The biological effects of AAs depend mainly on their biotransformation into reactive metabolites or into N-acetylated metabolites which are generally considered as less toxic. Although the activation of the aryl hydrocarbon receptor (AhR) pathway by certain carcinogenic AAs has been reported, the effects of their N-acetylated metabolites on the AhR have not been addressed. Here, we investigated whether carcinogenic AAs and their N-acetylated metabolites may activate/modulate the AhR pathway in the absence and/or the presence of a bona fide AhR ligand (benzo[a]pyrene/B(a)P]. In agreement with previous studies, we found that certain AAs activated the AhR in human liver and lung cells as assessed by an increase in cytochrome P450 1A1 (CYP1A1) expression and activity. Altogether, we report for the first time that these properties can be modulated by the N-acetylation status of the AA. Whereas 2-naphthylamine significantly activated the AhR and induced CYP1A1 expression, its N-acetylated metabolite was less efficient. In contrast, the N-acetylated metabolite of 2-aminofluorene was able to significantly activate AhR, whereas the parent AA, 2-aminofluorene, did not. In the presence of B(a)P, activation of AhR or antagonist effects were observed depending on the AA or its N-acetylated metabolite. Activation and/or modulation of the AhR pathway by AAs and their N-acetylated metabolites may represent a novel mechanism contributing to the toxicological effects of AAs. More broadly, our data suggest biological interactions between AAs and other classes of xenobiotics through the AhR pathway. FAU - Juricek, Ludmila AU - Juricek L AD - INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Peres, 75006, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, 45 rue des Saints-Peres, 75006, Paris, France. FAU - Bui, Linh-Chi AU - Bui LC AD - CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Universite Paris Diderot, Sorbonne Paris Cite, 4 rue Marie-Andree Lagroua Weill Halle, 75213, Paris, France. FAU - Busi, Florent AU - Busi F AD - CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Universite Paris Diderot, Sorbonne Paris Cite, 4 rue Marie-Andree Lagroua Weill Halle, 75213, Paris, France. FAU - Pierre, Stephane AU - Pierre S AD - INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Peres, 75006, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, 45 rue des Saints-Peres, 75006, Paris, France. FAU - Guyot, Erwan AU - Guyot E AD - INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Peres, 75006, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, 45 rue des Saints-Peres, 75006, Paris, France. FAU - Lamouri, Aazdine AU - Lamouri A AD - Laboratoire ITODYS, CNRS UMR 7086, Universite Paris Diderot, Sorbonne Paris Cite, 15, rue Jean-Antoine de Baif, 75013, Paris, France. FAU - Dupret, Jean-Marie AU - Dupret JM AD - CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Universite Paris Diderot, Sorbonne Paris Cite, 4 rue Marie-Andree Lagroua Weill Halle, 75213, Paris, France. FAU - Barouki, Robert AU - Barouki R AD - INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Peres, 75006, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, 45 rue des Saints-Peres, 75006, Paris, France. AD - Service de biochimie metabolique, AP-HP, Hopital Necker-Enfants Malades, 149 rue de Sevres, 75743, Paris, France. FAU - Coumoul, Xavier AU - Coumoul X AD - INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Peres, 75006, Paris, France. xavier.coumoul@parisdescartes.fr. AD - Universite Paris Descartes, Sorbonne Paris Cite, 45 rue des Saints-Peres, 75006, Paris, France. xavier.coumoul@parisdescartes.fr. FAU - Rodrigues-Lima, Fernando AU - Rodrigues-Lima F AD - CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Universite Paris Diderot, Sorbonne Paris Cite, 4 rue Marie-Andree Lagroua Weill Halle, 75213, Paris, France. fernando.rodrigues-lima@univ-paris-diderot.fr. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140917 PL - Germany TA - Arch Toxicol JT - Archives of toxicology JID - 0417615 RN - 0 (Aminobiphenyl Compounds) RN - 0 (Carcinogens) RN - 0 (Fluorenes) RN - 0 (Receptors, Aryl Hydrocarbon) RN - 16054949HJ (4-biphenylamine) RN - 3417WMA06D (Benzo(a)pyrene) RN - 3A69OS195N (2-aminofluorene) RN - CKR7XL41N4 (2-Naphthylamine) RN - EC 1.14.14.1 (CYP1A1 protein, human) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A1) SB - IM MH - 2-Naphthylamine/administration & dosage/metabolism/toxicity MH - Acetylation MH - Aminobiphenyl Compounds/administration & dosage/metabolism/toxicity MH - Benzo(a)pyrene/administration & dosage/pharmacology MH - Carcinogens/metabolism/*toxicity MH - Cell Line MH - Cytochrome P-450 CYP1A1/*genetics/metabolism MH - Fluorenes/administration & dosage/metabolism/toxicity MH - Gene Expression Regulation, Enzymologic/*drug effects MH - Hep G2 Cells MH - Humans MH - Liver/drug effects/metabolism MH - Lung/drug effects/metabolism MH - Receptors, Aryl Hydrocarbon/*drug effects/metabolism OTO - NOTNLM OT - Acetylation OT - Aromatic amines OT - Aryl hydrocarbon receptor OT - Benzo[a]pyrene OT - Metabolism OT - Mixture EDAT- 2014/09/17 06:00 MHDA- 2016/09/17 06:00 CRDT- 2014/09/17 06:00 PHST- 2014/05/26 00:00 [received] PHST- 2014/09/04 00:00 [accepted] PHST- 2014/09/17 06:00 [entrez] PHST- 2014/09/17 06:00 [pubmed] PHST- 2016/09/17 06:00 [medline] AID - 10.1007/s00204-014-1367-7 [pii] AID - 10.1007/s00204-014-1367-7 [doi] PST - ppublish SO - Arch Toxicol. 2015 Dec;89(12):2403-12. doi: 10.1007/s00204-014-1367-7. Epub 2014 Sep 17.