untitled
<OAI-PMH schemaLocation=http://www.openarchives.org/OAI/2.0/OAI-PMH.xsd>
<responseDate>2015-02-24T12:01:38Z</responseDate>
<request identifier=oai:HAL:hal-00688369v1 verb=GetRecord metadataPrefix=oai_dc>http://api.archives-ouvertes.fr/oai/hal/</request>
<GetRecord>
<record>
<header>
<identifier>oai:HAL:hal-00688369v1</identifier>
<datestamp>2014-10-13</datestamp>
<setSpec>type:ART</setSpec>
<setSpec>subject:sdv</setSpec>
<setSpec>collection:UNIV-AG</setSpec>
<setSpec>collection:IFR140</setSpec>
<setSpec>collection:UNIV-RENNES1</setSpec>
<setSpec>collection:IRSET</setSpec>
</header>
<metadata><dc>
<publisher>HAL CCSD</publisher>
<title lang=en>UDP-glucuronosyltransferase-mediated metabolic activation of the tobacco carcinogen 2-amino-9H-pyrido[2,3-b]indole.</title>
<creator>Tang, Yijin</creator>
<creator>Lemaster, David</creator>
<creator>Nauwelaers, Gwendoline</creator>
<creator>Gu, Dan</creator>
<creator>Langouët, Sophie</creator>
<creator>Turesky, Robert J.</creator>
<contributor>Signalisation et modélisation de la fibrose hépatique ; Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; INSERM - École Nationale de la Santé Publique - Université de Rennes 1 (UR1) - Université des Antilles et de la Guyane (UAG) - Structure Fédérative de Recherche en Biologie-Santé de Rennes (Biosit) ; Université de Rennes 1 (UR1) - INSERM - CNRS - INSERM - CNRS - INSERM - École Nationale de la Santé Publique - Université de Rennes 1 (UR1) - Université des Antilles et de la Guyane (UAG) - Structure Fédérative de Recherche en Biologie-Santé de Rennes (Biosit) ; Université de Rennes 1 (UR1) - INSERM - CNRS - INSERM - CNRS</contributor>
<description>International audience</description>
<source>Journal of Biological Chemistry</source>
<publisher>American Society for Biochemistry and Molecular Biology</publisher>
<identifier>hal-00688369</identifier>
<identifier>https://hal.archives-ouvertes.fr/hal-00688369</identifier>
<source>https://hal.archives-ouvertes.fr/hal-00688369</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>
<identifier>PUBMED : 22393056</identifier>
<language>en</language>
<subject lang=it>Metabolism</subject>
<subject lang=it>UDP-Glucuronosyltransferase</subject>
<subject lang=it>heterocyclic aromatic amine</subject>
<subject lang=it>tobacco carcinogen</subject>
<subject>[SDV.BBM] Life Sciences/Biochemistry, Molecular Biology</subject>
<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-hydroxy-amino-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, N2-(β-D-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N2-Gl) and N2-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON2-Gl). HONH-AαC also underwent glucuronidation to form a novel O-glucuronide conjugate, O-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN2-O-Gl). AαC-HN2-O-Gl is a biologically reactive metabolite that bound to calf thymus DNA (pH 5.0 or pH 7.0) to form the N-(deoxyguanosin-8-yl)-AαC (dG-C8-AαC) adduct at 20 to 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 (Vmax/Km) at forming AαC-N2-Gl (0.67 μL mg protein-1 min-1), UGT1A9 was most catalytically efficient at forming AαC-HN-O-Gl (77.1 μL mg protein-1 min-1), whereas, UGT1A1 was most efficient at forming AαC-HON2-Gl (5.0 μL mg protein-1 min-1). Human hepatocytes produced AαC-N2-Gl and AαC-HN2-O-Gl in abundant quantities, but AαC-HON2-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.</description>
<date>2012-03-05</date>
</dc>
</metadata>
</record>
</GetRecord>
</OAI-PMH>
