title: Human T lymphocytes bioactivate heterocyclic aromatic amines by forming DNA adducts.
abstract: Heterocyclic aromatic amines (HAA) are formed in cooked meat, poultry and fish but also arise in tobacco smoke and exhaust gases. HAA are potential human carcinogens, which require metabolic activation to exert their genotoxicity. Human tissues can bioactivate HAA to produce reactive intermediates that bind to DNA. HAA DNA adduct formation occurs in human hepatocytes; however, the potential of HAA to form DNA adducts has not been investigated in human T lymphocytes. In this study, we investigated the ability of human T lymphocytes activated with PMA/Ionomycin or CD3/CD28 to express functional CYP1 activity and bioactivate three major HAA: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-9H-pyrido[2,3-b]indole (AαC) to form DNA adducts. Adducts were measured by ultraperformance liquid chromatography-electrospray ionization/multistage scan mass spectrometry. The highest level of DNA adducts occurred for AαC (16 adducts per 109nucleotides), followed by PhIP (9 adducts per 109nucleotides). In contrast, DNA adducts formed from MeIQx and the structurally related aromatic amine 4-aminobiphenyl, a known human carcinogen, were below the limit of detection (< 3 adducts per 109nucleotides). Moreover, we demonstrate that AαC is a potent inducer of CYP1A1 and CYP1B1 activity through a transcriptional mechanism involving the AhR pathway. Overall, our results highlight the capacity of activated human T lymphocytes to more efficiently bioactivate AαC to form DNA adducts than other prominent HAA or 4-ABP. Environ. Mol. Mutagen. 57:656-667, 2016. © 2016 Wiley Periodicals, Inc.
authors: Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche en Santé Environnement et Travail (IRSET), Université de Rennes 1, UMS 3480 Biosit, Rennes, F-35043, France.|ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, Fougères, France.
authors: Medjda
authors: M
authors: Bellamri
authors: ANSES, French Agency for Food, Environmental and Occupational Health & Safety, Fougères Laboratory, Toxicology of Contaminants Unit, Fougères, France.
authors: Ludovic
authors: 0000-0003-3494-4109
authors: L
authors: Le Hegarat
authors: Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche en Santé Environnement et Travail (IRSET), Université de Rennes 1, UMS 3480 Biosit, Rennes, F-35043, France.
authors: Laurent
authors: L
authors: Vernhet
authors: Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche en Santé Environnement et Travail (IRSET), Université de Rennes 1, UMS 3480 Biosit, Rennes, F-35043, France.
authors: Georges
authors: G
authors: Baffet
authors: Masonic Cancer Center and Department of Medicinal Chemistry, Cancer and Cardiology Research Building, University of Minnesota, 2231 6th Street, Minneapolis, Minnesota, 55455.
authors: Robert J
authors: RJ
authors: Turesky
authors: Institut National de la Santé et de la Recherche Médicale (Inserm), U1085, Institut de Recherche en Santé Environnement et Travail (IRSET), Université de Rennes 1, UMS 3480 Biosit, Rennes, F-35043, France.
authors: Sophie
authors: S
authors: Langouët
mesh_terms: D065767:Activation, Metabolic; D002243:Carbolines / Q000378:metabolism* / Q000633:toxicity; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D065633:Cytochrome P-450 CYP1B1 / Q000096:biosynthesis; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000633:toxicity; D011810:Quinoxalines / Q000378:metabolism* / Q000633:toxicity; D060888:Real-Time Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002243:Carbolines; D018736:DNA Adducts; D007093:Imidazoles; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C017822:2-amino-9H-pyrido(2,3-b)indole
keywords: 2-amino-9H-pyrido[2,3-b]indole; carcinogen metabolism; cytochrome P450; genotoxicity