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<title lang=en>UDP-glucuronosyltransferase-mediated metabolic activation of the tobacco carcinogen 2-amino-9H-pyrido[2,3-b]indole</title>
<creator>Tang, Y.</creator>
<creator>Lemaster, David</creator>
<creator>Nauwelaers, Gwendoline</creator>
<creator>Gu, D.</creator>
<creator>Langouët, Sophie</creator>
<creator>Turesky, Robert J</creator>
<contributor>Department of Civil and Environmental Engineering ; PennState University [Pennsylvania] (PSU)</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>Unité de Toxicologie des Contaminants ; ANSES</contributor>
<description>International audience</description>
<source>ISSN: 0021-9258</source>
<source>EISSN: 1083-351X</source>
<source>Journal of Biological Chemistry</source>
<publisher>American Society for Biochemistry and Molecular Biology</publisher>
<identifier>hal-00696860</identifier>
<identifier>https://hal-anses.archives-ouvertes.fr/hal-00696860</identifier>
<source>https://hal-anses.archives-ouvertes.fr/hal-00696860</source>
<source>Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2012, 287 (18), pp.14960-14972. 〈10.1074/jbc.M111.320093〉</source>
<identifier>DOI : 10.1074/jbc.M111.320093</identifier>
<relation>info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M111.320093</relation>
<identifier>PUBMED : 22393056</identifier>
<relation>info:eu-repo/semantics/altIdentifier/pmid/22393056</relation>
<language>en</language>
<subject lang=es>carcinogèen</subject>
<subject lang=es>carcinogenicité</subject>
<subject lang=es>toxicologie</subject>
<subject lang=es>tobacco</subject>
<subject lang=es>carcinogen</subject>
<subject lang=es>2-amino-9H-pyrido[2</subject>
<subject lang=es>3-b]indole</subject>
<subject lang=es>tabac</subject>
<subject lang=es>toxicité</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 (AαC) is a carcinogenic heterocyclic aromatic amine (HAA) that arises in tobacco smoke. UDP-glucuronosyltransferases (UGTs) are important enzymes that detoxicate many procarcinogens, including HAAs. UGTs compete with P450 enzymes, which bioactivate HAAs by N-hydroxylation of the exocyclic amine group; the resultant N-hydroxy-HAA metabolites form covalent adducts with DNA. We have characterized the UGT-catalyzed metabolic products of AαC and the genotoxic metabolite 2-hydroxyamino-9H-pyrido[2,3- b]indole (HONH-AαC) formed with human liver microsomes, recombinant human UGT isoforms, and human hepatocytes. The structures of the metabolites were elucidated by 1H NMR and mass spectrometry. AαC and HONH-AαC underwent glucuronidation by UGTs to form, respectively, N 2-(β- D-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N 2-Gl) and N 2-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b] indole (AαC-HON 2-Gl). HONH-AαC also underwent glucuronidation to form a novel O-linked glucuronide conjugate, O-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN 2-O-Gl). AαC-HN 2-O-Gl is a biologically reactive metabolite and binds to calf thymus DNA (pH 5.0 or 7.0) to form the N-(deoxyguanosin-8-yl)-AαC adduct at 20-50-fold higher levels than the adduct levels formed with HONH-AαC. Major UGT isoforms were examined for their capacity to metabolize AαC and HONH-AαC. UGT1A4 was the most catalytically efficient enzyme (V max/K m) at forming AαC-N 2-Gl (0.67 μl*min -1*mg of protein -1), and UGT1A9 was most catalytically efficient at forming AαC-HN-O-Gl (77.1 μl*min -1*mg of protein -1), whereas UGT1A1 was most efficient at forming AαC-HON 2-Gl (5.0 μl*min -1*mg of protein -1). Human hepatocytes produced AαC-N 2-Gl and AαC-HN 2-O-Gl in abundant quantities, but AαC-HON 2-Gl was a minor product. Thus, UGTs, usually important enzymes in the detoxication of many procarcinogens, serve as a mechanism of bioactivation of HONH-AαC. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.</description>
<date>2012</date>
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