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<title lang=en>Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AalphaC) in Primary Human Hepatocytes</title>
<creator>Bellamri, Medjda</creator>
<creator>Le Hegarat, Ludovic</creator>
<creator>Turesky, Robert J</creator>
<creator>Langouët, Sophie</creator>
<contributor>Anses Laboratoire de Fougères ; ANSES</contributor>
<contributor>Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )</contributor>
<contributor>Masonic Cancer Center ; University of Minnesota [Minneapolis]</contributor>
<contributor>Institut National de la Santé et de la Recherche Médicale (INSERM)</contributor>
<contributor>INSERM</contributor>
<description>International audience</description>
<source>ISSN: 0893-228X</source>
<source>EISSN: 1520-5010</source>
<source>Chemical Research in Toxicology</source>
<publisher>American Chemical Society</publisher>
<identifier>anses-01419468</identifier>
<identifier>https://hal-anses.archives-ouvertes.fr/anses-01419468</identifier>
<identifier>https://hal-anses.archives-ouvertes.fr/anses-01419468/document</identifier>
<identifier>https://hal-anses.archives-ouvertes.fr/anses-01419468/file/Bellamri%20et%20al.%20-%202016%20-%20Metabolism%20of%20the%20Tobacco%20Carcinogen%202-Amino-9H-py.pdf</identifier>
<source>https://hal-anses.archives-ouvertes.fr/anses-01419468</source>
<source>Chemical Research in Toxicology, American Chemical Society, 2016, 30 (2), pp.657-668. 〈http://pubs.acs.org/doi/abs/10.1021/acs.chemrestox.6b00394〉. 〈10.1021/acs.chemrestox.6b00394〉</source>
<identifier>DOI : 10.1021/acs.chemrestox.6b00394</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.chemrestox.6b00394</relation>
<identifier>PUBMED : 27976871</identifier>
<relation>info:eu-repo/semantics/altIdentifier/pmid/27976871</relation>
<source>http://pubs.acs.org/doi/abs/10.1021/acs.chemrestox.6b00394</source>
<language>en</language>
<subject lang=en>human hepatocyte</subject>
<subject lang=en>toxicity</subject>
<subject lang=en>metabolism</subject>
<subject lang=en>carcinogen</subject>
<subject lang=en>heterocyclic aromatic amine</subject>
<subject lang=fr>toxicité</subject>
<subject lang=fr>metabolisme</subject>
<subject lang=fr>amine aromatique hétérocyclique</subject>
<subject lang=fr>carcinogène</subject>
<subject lang=fr>hépatocyte humain</subject>
<subject>[SDV.TOX] Life Sciences [q-bio]/Toxicology</subject>
<type>info:eu-repo/semantics/article</type>
<type>Journal articles</type>
<description lang=en>2-Amino-9H-pyrido[2,3-b]indole (AalphaC) is the most abundant carcinogenic heterocyclic aromatic amine (HAA) formed in mainstream tobacco smoke. AalphaC is a liver carcinogen in rodents, but its carcinogenic potential in humans is not known. To obtain a better understanding of the genotoxicity of AalphaC in humans, we have investigated its metabolism and its ability to form DNA adducts in human hepatocytes. Primary human hepatocytes were treated with AalphaC at doses ranging from 0.1-50 muM, and the metabolites were characterized by ultra-performance LC/ion trap multistage mass spectrometry (UPLC/MSn). Six major metabolites were identified: a ring-oxidized doubly conjugated metabolite, N2-acetyl-2-amino-9H-pyrido[2,3-b]indole-6-yl-oxo-(beta-d-glucuronic acid) (N2-acetyl-AalphaC-6-O-Gluc); two ring-oxidized glucuronide (Gluc) conjugates: 2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(beta-d-glucuronic acid) (AalphaC-3-O-Gluc) and 2-amino-9H-pyrido[2,3-b]indol-6-yl-oxo-(beta-d-glucuronic acid) (AalphaC-6-O-Gluc); two sulfate conjugates, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AalphaC-3-O-SO3H) and 2-amino-9H-pyrido[2,3-b]indol-6-yl sulfate (AalphaC-6-O-SO3H); and the Gluc conjugate, N2-(beta-d-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AalphaC-N2-Gluc). In addition, four minor metabolites were identified: N2-acetyl-9H-pyrido[2,3-b]indol-3-yl sulfate (N2-acetyl-AalphaC-3-O-SO3H), N2-acetyl-9H-pyrido[2,3-b]indol-6-yl sulfate (N2-acetyl-AalphaC-6-O-SO3H), N2-acetyl-2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(beta-d-glucuronic acid) (N2-acetyl-AalphaC-3-O-Gluc), and O-(beta-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AalphaC-HN2-O-Gluc). The latter metabolite, AalphaC-HN2-O-Gluc is a reactive intermediate that binds to DNA to form the covalent adduct N-(2'-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AalphaC). Preincubation of hepatocytes with furafylline, a selective mechanism-based inhibitor of P450 1A2, resulted in a strong decrease in the formation of AalphaC-HN2-O-Gluc and a concomitant decrease in DNA adduct formation. Our findings describe the major pathways of metabolism of AalphaC in primary human hepatocytes and reveal the importance of N-acetylation and glucuronidation in metabolism of AalphaC. P450 1A2 is a major isoform involved in the bioactivation of AalphaC to form the reactive AalphaC-HN2-O-Gluc conjugate and AalphaC-DNA adducts.</description>
<date>2016</date>
</dc>
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