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.
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Acknowledgments
This work was supported by the Université Paris Descartes, Université Paris Diderot, INSERM (Institut National de la Santé et de la Recherche Médicale), the CNRS (Centre National de la Recherche Scientifique), the ANSES (Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail, Funding), the Fondation pour la Recherche Médicale (Post doctoral fellowship, Linh-Chi Bui), the Ligue contre le Cancer (Postdoctoral fellowship, Linh-Chi Bui), the Assistance Publique-Hôpitaux de Paris (Erwan Guyot) and the Région Ile de France (PhD fellowships: Ludmila Juricek, Stéphane Pierre). We thank Dr. Lawrence Aggerbeck and Martin Cairns for his critical reading of this manuscript.
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Ludmila Juricek and Linh-Chi Bui have contributed equally to this work.
Xavier Coumoul and Rodrigues-Lima share senior authorship.
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Supplementary Fig. 1: Measurement of the EROD activity of CYP1A1-XRE-GLuc HepG2 cells following treatment with AAs and BaP. Cells were treated for 8 h with 25 µM of the compounds. EROD activity in cultured cells was measured by the fluorescence of resorufin generated by the conversion of ethoxyresorufin by CYP using a fluorescence plate reader (Coumoul X et al. 2001). Values are the mean ± SEM (n = 4). * p < 0.05; ** p < 0.01 and *** p < 0.001 as compared to corresponding control group. (TIFF 1238 kb)
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Juricek, L., Bui, LC., Busi, F. et al. Activation of the aryl hydrocarbon receptor by carcinogenic aromatic amines and modulatory effects of their N-acetylated metabolites. Arch Toxicol 89, 2403–2412 (2015). https://doi.org/10.1007/s00204-014-1367-7
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DOI: https://doi.org/10.1007/s00204-014-1367-7