title: Activation of the aryl hydrocarbon receptor by carcinogenic aromatic amines and modulatory effects of their N-acetylated metabolites.
abstract: 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.
authors.affiliation: INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Pères, 75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006, Paris, France.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Juricek
authors.affiliation: CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Université Paris Diderot, Sorbonne Paris Cité, 4 rue Marie-Andrée Lagroua Weill Hallé, 75213, Paris, France.
authors.forename: Linh-Chi
authors.initials: LC
authors.lastname: Bui
authors.affiliation: CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Université Paris Diderot, Sorbonne Paris Cité, 4 rue Marie-Andrée Lagroua Weill Hallé, 75213, Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Busi
authors.affiliation: INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Pères, 75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pierre
authors.affiliation: INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Pères, 75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006, Paris, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Guyot
authors.affiliation: Laboratoire ITODYS, CNRS UMR 7086, Université Paris Diderot, Sorbonne Paris Cité, 15, rue Jean-Antoine de Baïf, 75013, Paris, France.
authors.forename: Aazdine
authors.initials: A
authors.lastname: Lamouri
authors.affiliation: CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Université Paris Diderot, Sorbonne Paris Cité, 4 rue Marie-Andrée Lagroua Weill Hallé, 75213, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Dupret
authors.affiliation: INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Pères, 75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006, Paris, France.|Service de biochimie métabolique, AP-HP, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743, Paris, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Barouki
authors.affiliation: INSERM UMR-S 1124, Toxicologie Pharmacologie et Signalisation cellulaire, 45 rue des Saints-Pères, 75006, Paris, France. xavier.coumoul@parisdescartes.fr.|Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006, Paris, France. xavier.coumoul@parisdescartes.fr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Coumoul
authors.affiliation: CNRS EAC 4413, Biologie Fonctionnelle et Adaptative, Université Paris Diderot, Sorbonne Paris Cité, 4 rue Marie-Andrée Lagroua Weill Hallé, 75213, Paris, France. fernando.rodrigues-lima@univ-paris-diderot.fr.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
mesh_terms: D015081:2-Naphthylamine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D000107:Acetylation; D000611:Aminobiphenyl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D005449:Fluorenes / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D005449:Fluorenes; D018336:Receptors, Aryl Hydrocarbon; C006757:4-biphenylamine; D001564:Benzo(a)pyrene; C012177:2-aminofluorene; D015081:2-Naphthylamine; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1
keywords: Acetylation; Aromatic amines; Aryl hydrocarbon receptor; Benzo[a]pyrene; Metabolism; Mixture