Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase
Identifieur interne : 001D07 ( Istex/Corpus ); précédent : 001D06; suivant : 001D08Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase
Auteurs : Chakib El Adlouni ; Eric Pinelli ; Brigitte Azémar ; Driss Zaoui ; Philippe Beaune ; Annie Pfohl-LeszkowiczSource :
- Environmental and Molecular Mutagenesis [ 0893-6692 ] ; 2000.
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Abstract
Ochratoxin A (OTA), a mycotoxin that induces nephrotoxicity and urinary tract tumors, is genotoxic and can be metabolized not only by different cytochromes P450 (CYP) but also by peroxidases involved in the arachidonic cascade, although the exact nature of the metabolites involved in the genotoxic process is still unknown. In order to establish the relation between OTA genotoxicity and the formation of metabolites, we chose three experimental models: kidney microsomes from rabbit, human bronchial epithelial cells, and microsomes from yeast that specifically express the human cytochrome P450 2C9 or 2B6 genes. OTA‐DNA adducts were analyzed by 32P postlabeling and the OTA derivatives formed were isolated by HPLC after incubation of OTA in the presence of: (1) kidney microsomes from rabbit pretreated or not with phenobarbital (PB); (2) human pulmonary epithelial cells simultaneously pretreated (or not) with PB alone or in the presence of ethacrynic acid (EA); (3) microsomes expressing CYP 2B6 and 2C9. PB pretreatment significantly increased DNA adducts formed after OTA treatment, both in the presence of kidney microsomes and bronchial epithelial cells, and induced the formation of new adducts. Ethacrynic acid, which inhibits microsomal glutathione‐S‐transferase, reduced DNA adduct level. DNA adducts were detected when OTA were incubated with microsomes expressing human CYP 2C9 but not with those expressing CYP 2B6. Several metabolites detected by HPLC were increased after PB treatment. Some of them could be related to DNA‐adduct formation. In conclusion, OTA biotransformation, enhanced by PB pretreatment, increased DNA‐adduct formation through pathways involving microsomal glutathion‐S‐transferase and CYP 2C9. Environ. Mol. Mutagen. 35:123–131, 2000 © 2000 Wiley‐Liss, Inc.
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DOI: 10.1002/(SICI)1098-2280(2000)35:2<123::AID-EM7>3.0.CO;2-L
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of CYP 2C9 and microsomal glutathione‐S‐transferase</title><author><name sortKey="El Adlouni, Chakib" sort="El Adlouni, Chakib" uniqKey="El Adlouni C" first="Chakib" last="El Adlouni">Chakib El Adlouni</name><affiliation><mods:affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</mods:affiliation></affiliation></author><author><name sortKey="Pinelli, Eric" sort="Pinelli, Eric" uniqKey="Pinelli E" first="Eric" last="Pinelli">Eric Pinelli</name><affiliation><mods:affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</mods:affiliation></affiliation></author><author><name sortKey="Azemar, Brigitte" sort="Azemar, Brigitte" uniqKey="Azemar B" first="Brigitte" last="Azémar">Brigitte Azémar</name><affiliation><mods:affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</mods:affiliation></affiliation></author><author><name sortKey="Zaoui, Driss" sort="Zaoui, Driss" uniqKey="Zaoui D" first="Driss" last="Zaoui">Driss Zaoui</name><affiliation><mods:affiliation>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</mods:affiliation></affiliation></author><author><name sortKey="Beaune, Philippe" sort="Beaune, Philippe" uniqKey="Beaune P" first="Philippe" last="Beaune">Philippe Beaune</name><affiliation><mods:affiliation>Laboratoire Toxicologie Moléculaire, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Pfohl Eszkowicz, Annie" sort="Pfohl Eszkowicz, Annie" uniqKey="Pfohl Eszkowicz A" first="Annie" last="Pfohl-Leszkowicz">Annie Pfohl-Leszkowicz</name><affiliation><mods:affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</mods:affiliation></affiliation><affiliation><mods:affiliation>ENSAT, Laboratoire de Toxicologie et 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Mol. Mutagen.</title><idno type="ISSN">0893-6692</idno><idno type="eISSN">1098-2280</idno><imprint><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="2000">2000</date><biblScope unit="volume">35</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="123">123</biblScope><biblScope unit="page" to="131">131</biblScope></imprint><idno type="ISSN">0893-6692</idno></series><idno type="istex">D79E61677114C0FE622ADEC3446AABDE265C4E1A</idno><idno type="DOI">10.1002/(SICI)1098-2280(2000)35:2<123::AID-EM7>3.0.CO;2-L</idno><idno type="ArticleID">EM7</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0893-6692</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>DNA adducts</term><term>human CYP 2B6</term><term>human CYP 2C9</term><term>human bronchial epithelial cells</term><term>kidney rabbit microsomes</term><term>microsomal glutathione‐S‐transferase</term><term>ochratoxin A</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Ochratoxin A (OTA), a mycotoxin that induces nephrotoxicity and urinary tract tumors, is genotoxic and can be metabolized not only by different cytochromes P450 (CYP) but also by peroxidases involved in the arachidonic cascade, although the exact nature of the metabolites involved in the genotoxic process is still unknown. In order to establish the relation between OTA genotoxicity and the formation of metabolites, we chose three experimental models: kidney microsomes from rabbit, human bronchial epithelial cells, and microsomes from yeast that specifically express the human cytochrome P450 2C9 or 2B6 genes. OTA‐DNA adducts were analyzed by 32P postlabeling and the OTA derivatives formed were isolated by HPLC after incubation of OTA in the presence of: (1) kidney microsomes from rabbit pretreated or not with phenobarbital (PB); (2) human pulmonary epithelial cells simultaneously pretreated (or not) with PB alone or in the presence of ethacrynic acid (EA); (3) microsomes expressing CYP 2B6 and 2C9. PB pretreatment significantly increased DNA adducts formed after OTA treatment, both in the presence of kidney microsomes and bronchial epithelial cells, and induced the formation of new adducts. Ethacrynic acid, which inhibits microsomal glutathione‐S‐transferase, reduced DNA adduct level. DNA adducts were detected when OTA were incubated with microsomes expressing human CYP 2C9 but not with those expressing CYP 2B6. Several metabolites detected by HPLC were increased after PB treatment. Some of them could be related to DNA‐adduct formation. In conclusion, OTA biotransformation, enhanced by PB pretreatment, increased DNA‐adduct formation through pathways involving microsomal glutathion‐S‐transferase and CYP 2C9. Environ. Mol. Mutagen. 35:123–131, 2000 © 2000 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Chakib El Adlouni</name><affiliations><json:string>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</json:string><json:string>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</json:string></affiliations></json:item><json:item><name>Eric Pinelli</name><affiliations><json:string>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</json:string></affiliations></json:item><json:item><name>Brigitte Azémar</name><affiliations><json:string>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</json:string></affiliations></json:item><json:item><name>Driss Zaoui</name><affiliations><json:string>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</json:string></affiliations></json:item><json:item><name>Philippe Beaune</name><affiliations><json:string>Laboratoire Toxicologie Moléculaire, Paris, France</json:string></affiliations></json:item><json:item><name>Annie Pfohl‐Leszkowicz</name><affiliations><json:string>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</json:string><json:string>ENSAT, Laboratoire de Toxicologie et Sécurité Alimentaire, avenue de l'Agrobiopole BP 107, F‐31326 Auzeville‐Tolosane, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>DNA adducts</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ochratoxin A</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>human bronchial epithelial cells</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>kidney rabbit microsomes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>human CYP 2C9</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>human CYP 2B6</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>microsomal glutathione‐S‐transferase</value></json:item></subject><articleId><json:string>EM7</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Ochratoxin A (OTA), a mycotoxin that induces nephrotoxicity and urinary tract tumors, is genotoxic and can be metabolized not only by different cytochromes P450 (CYP) but also by peroxidases involved in the arachidonic cascade, although the exact nature of the metabolites involved in the genotoxic process is still unknown. In order to establish the relation between OTA genotoxicity and the formation of metabolites, we chose three experimental models: kidney microsomes from rabbit, human bronchial epithelial cells, and microsomes from yeast that specifically express the human cytochrome P450 2C9 or 2B6 genes. OTA‐DNA adducts were analyzed by 32P postlabeling and the OTA derivatives formed were isolated by HPLC after incubation of OTA in the presence of: (1) kidney microsomes from rabbit pretreated or not with phenobarbital (PB); (2) human pulmonary epithelial cells simultaneously pretreated (or not) with PB alone or in the presence of ethacrynic acid (EA); (3) microsomes expressing CYP 2B6 and 2C9. PB pretreatment significantly increased DNA adducts formed after OTA treatment, both in the presence of kidney microsomes and bronchial epithelial cells, and induced the formation of new adducts. Ethacrynic acid, which inhibits microsomal glutathione‐S‐transferase, reduced DNA adduct level. DNA adducts were detected when OTA were incubated with microsomes expressing human CYP 2C9 but not with those expressing CYP 2B6. Several metabolites detected by HPLC were increased after PB treatment. Some of them could be related to DNA‐adduct formation. In conclusion, OTA biotransformation, enhanced by PB pretreatment, increased DNA‐adduct formation through pathways involving microsomal glutathion‐S‐transferase and CYP 2C9. Environ. Mol. Mutagen. 35:123–131, 2000 © 2000 Wiley‐Liss, Inc.</abstract><qualityIndicators><score>8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1799</abstractCharCount><pdfWordCount>5751</pdfWordCount><pdfCharCount>36074</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>259</abstractWordCount></qualityIndicators><title>Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase</title><refBibs><json:item><author><json:item><name>AM Bendele</name></json:item><json:item><name>WW Carlton</name></json:item><json:item><name>P Krogh</name></json:item><json:item><name>EB Lillehoj</name></json:item></author><host><volume>75</volume><pages><last>742</last><first>733</first></pages><author></author><title>J Natl Cancer Inst</title></host><title>Ochratoxin A carcinogenesis in the (C57BL/6J/C3H) F1 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research</json:string><json:string>toxicology</json:string></scienceMetrix></categories><publicationDate>2000</publicationDate><copyrightDate>2000</copyrightDate><doi><json:string>10.1002/(SICI)1098-2280(2000)35:2>123::AID-EM7>3.0.CO;2-L</json:string></doi><id>D79E61677114C0FE622ADEC3446AABDE265C4E1A</id><score>0.19514361</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/D79E61677114C0FE622ADEC3446AABDE265C4E1A/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/D79E61677114C0FE622ADEC3446AABDE265C4E1A/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/D79E61677114C0FE622ADEC3446AABDE265C4E1A/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><availability><p>Copyright © 2000 Wiley‐Liss, Inc.</p></availability><date>2000</date></publicationStmt><notesStmt><note>French Ministry of Research and Universities - No. Action Spécifique 97‐1477; No. DRED 1970;</note><note>Midi‐Pyrénées Region - No. 9408014; No. 9600487; No. 9609624;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase</title><author xml:id="author-1"><persName><forename type="first">Chakib</forename><surname>El Adlouni</surname></persName><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation><affiliation>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</affiliation></author><author xml:id="author-2"><persName><forename type="first">Eric</forename><surname>Pinelli</surname></persName><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">Brigitte</forename><surname>Azémar</surname></persName><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">Driss</forename><surname>Zaoui</surname></persName><affiliation>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</affiliation></author><author xml:id="author-5"><persName><forename type="first">Philippe</forename><surname>Beaune</surname></persName><affiliation>Laboratoire Toxicologie Moléculaire, Paris, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">Annie</forename><surname>Pfohl‐Leszkowicz</surname></persName><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation><affiliation>ENSAT, Laboratoire de Toxicologie et Sécurité Alimentaire, avenue de l'Agrobiopole BP 107, F‐31326 Auzeville‐Tolosane, France</affiliation></author></analytic><monogr><title level="j">Environmental and Molecular Mutagenesis</title><title level="j" type="abbrev">Environ. Mol. Mutagen.</title><idno type="pISSN">0893-6692</idno><idno type="eISSN">1098-2280</idno><idno type="DOI">10.1002/(ISSN)1098-2280</idno><imprint><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="2000"></date><biblScope unit="volume">35</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="123">123</biblScope><biblScope unit="page" to="131">131</biblScope></imprint></monogr><idno type="istex">D79E61677114C0FE622ADEC3446AABDE265C4E1A</idno><idno type="DOI">10.1002/(SICI)1098-2280(2000)35:2<123::AID-EM7>3.0.CO;2-L</idno><idno type="ArticleID">EM7</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2000</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Ochratoxin A (OTA), a mycotoxin that induces nephrotoxicity and urinary tract tumors, is genotoxic and can be metabolized not only by different cytochromes P450 (CYP) but also by peroxidases involved in the arachidonic cascade, although the exact nature of the metabolites involved in the genotoxic process is still unknown. In order to establish the relation between OTA genotoxicity and the formation of metabolites, we chose three experimental models: kidney microsomes from rabbit, human bronchial epithelial cells, and microsomes from yeast that specifically express the human cytochrome P450 2C9 or 2B6 genes. OTA‐DNA adducts were analyzed by 32P postlabeling and the OTA derivatives formed were isolated by HPLC after incubation of OTA in the presence of: (1) kidney microsomes from rabbit pretreated or not with phenobarbital (PB); (2) human pulmonary epithelial cells simultaneously pretreated (or not) with PB alone or in the presence of ethacrynic acid (EA); (3) microsomes expressing CYP 2B6 and 2C9. PB pretreatment significantly increased DNA adducts formed after OTA treatment, both in the presence of kidney microsomes and bronchial epithelial cells, and induced the formation of new adducts. Ethacrynic acid, which inhibits microsomal glutathione‐S‐transferase, reduced DNA adduct level. DNA adducts were detected when OTA were incubated with microsomes expressing human CYP 2C9 but not with those expressing CYP 2B6. Several metabolites detected by HPLC were increased after PB treatment. Some of them could be related to DNA‐adduct formation. In conclusion, OTA biotransformation, enhanced by PB pretreatment, increased DNA‐adduct formation through pathways involving microsomal glutathion‐S‐transferase and CYP 2C9. Environ. Mol. Mutagen. 35:123–131, 2000 © 2000 Wiley‐Liss, Inc.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>DNA adducts</term></item><item><term>ochratoxin A</term></item><item><term>human bronchial epithelial cells</term></item><item><term>kidney rabbit microsomes</term></item><item><term>human CYP 2C9</term></item><item><term>human CYP 2B6</term></item><item><term>microsomal glutathione‐S‐transferase</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1999-07-04">Received</change><change when="1999-11-01">Registration</change><change when="2000">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/D79E61677114C0FE622ADEC3446AABDE265C4E1A/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>John Wiley & Sons, Inc.</publisherName><publisherLoc>New York</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1098-2280</doi><issn type="print">0893-6692</issn><issn type="electronic">1098-2280</issn><idGroup><id type="product" value="EM"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="ENVIRONMENTAL AND MOLECULAR MUTAGENESIS">Environmental and Molecular Mutagenesis</title><title type="short">Environ. Mol. Mutagen.</title></titleGroup></publicationMeta><publicationMeta level="part" position="30"><doi origin="wiley" registered="yes">10.1002/(SICI)1098-2280(2000)35:2<>1.0.CO;2-J</doi><numberingGroup><numbering type="journalVolume" number="35">35</numbering><numbering type="journalIssue">2</numbering></numberingGroup><coverDate startDate="2000">2000</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="7" status="forIssue"><doi origin="wiley" registered="yes">10.1002/(SICI)1098-2280(2000)35:2<123::AID-EM7>3.0.CO;2-L</doi><idGroup><id type="unit" value="EM7"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2000 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="1999-07-04"></event><event type="manuscriptRevised" date="1999-09-06"></event><event type="manuscriptAccepted" date="1999-11-01"></event><event type="firstOnline" date="2000-03-09"></event><event type="publishedOnlineFinalForm" date="2000-03-09"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.2 mode:FullText source:HeaderRef result:HeaderRef" date="2010-03-06"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-24"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-17"></event></eventGroup><numberingGroup><numbering type="pageFirst">123</numbering><numbering type="pageLast">131</numbering></numberingGroup><correspondenceTo>ENSAT, Laboratoire de Toxicologie et Sécurité Alimentaire, avenue de l'Agrobiopole BP 107, F‐31326 Auzeville‐Tolosane, France</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:EM.EM7.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="5"></count><count type="tableTotal" number="2"></count><count type="referenceTotal" number="59"></count><count type="wordTotal" number="6708"></count></countGroup><titleGroup><title type="main" xml:lang="en">Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐<i>S</i>‐transferase</title><title type="short" xml:lang="en">Enhanced OTA Genotoxicity by Phenobarbital</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Chakib</givenNames><familyName>El Adlouni</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Eric</givenNames><familyName>Pinelli</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Brigitte</givenNames><familyName>Azémar</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Driss</givenNames><familyName>Zaoui</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Philippe</givenNames><familyName>Beaune</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>Annie</givenNames><familyName>Pfohl‐Leszkowicz</familyName></personName><contactDetails><email>leszkowicz@ensat.fr</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="FR" type="organization"><unparsedAffiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="MA" type="organization"><unparsedAffiliation>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="FR" type="organization"><unparsedAffiliation>Laboratoire Toxicologie Moléculaire, Paris, France</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">DNA adducts</keyword><keyword xml:id="kwd2">ochratoxin A</keyword><keyword xml:id="kwd3">human bronchial epithelial cells</keyword><keyword xml:id="kwd4">kidney rabbit microsomes</keyword><keyword xml:id="kwd5">human CYP 2C9</keyword><keyword xml:id="kwd6">human CYP 2B6</keyword><keyword xml:id="kwd7">microsomal glutathione‐<i>S</i>‐transferase</keyword></keywordGroup><fundingInfo><fundingAgency>French Ministry of Research and Universities</fundingAgency><fundingNumber>Action Spécifique 97‐1477</fundingNumber><fundingNumber>DRED 1970</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Midi‐Pyrénées Region</fundingAgency><fundingNumber>9408014</fundingNumber><fundingNumber>9600487</fundingNumber><fundingNumber>9609624</fundingNumber></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Ochratoxin A (OTA), a mycotoxin that induces nephrotoxicity and urinary tract tumors, is genotoxic and can be metabolized not only by different cytochromes P450 (CYP) but also by peroxidases involved in the arachidonic cascade, although the exact nature of the metabolites involved in the genotoxic process is still unknown. In order to establish the relation between OTA genotoxicity and the formation of metabolites, we chose three experimental models: kidney microsomes from rabbit, human bronchial epithelial cells, and microsomes from yeast that specifically express the human cytochrome P450 2C9 or 2B6 genes. OTA‐DNA adducts were analyzed by <sup>32</sup>P postlabeling and the OTA derivatives formed were isolated by HPLC after incubation of OTA in the presence of: (1) kidney microsomes from rabbit pretreated or not with phenobarbital (PB); (2) human pulmonary epithelial cells simultaneously pretreated (or not) with PB alone or in the presence of ethacrynic acid (EA); (3) microsomes expressing CYP 2B6 and 2C9. PB pretreatment significantly increased DNA adducts formed after OTA treatment, both in the presence of kidney microsomes and bronchial epithelial cells, and induced the formation of new adducts. Ethacrynic acid, which inhibits microsomal glutathione‐<i>S</i>‐transferase, reduced DNA adduct level. DNA adducts were detected when OTA were incubated with microsomes expressing human CYP 2C9 but not with those expressing CYP 2B6. Several metabolites detected by HPLC were increased after PB treatment. Some of them could be related to DNA‐adduct formation. In conclusion, OTA biotransformation, enhanced by PB pretreatment, increased DNA‐adduct formation through pathways involving microsomal glutathion‐<i>S</i>‐transferase and CYP 2C9. Environ. Mol. Mutagen. 35:123–131, 2000 © 2000 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Enhanced OTA Genotoxicity by Phenobarbital</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Phenobarbital increases DNA adduct and metabolites formed by ochratoxin A: Role of CYP 2C9 and microsomal glutathione‐S‐transferase</title></titleInfo><name type="personal"><namePart type="given">Chakib</namePart><namePart type="family">El Adlouni</namePart><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation><affiliation>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eric</namePart><namePart type="family">Pinelli</namePart><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Brigitte</namePart><namePart type="family">Azémar</namePart><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Driss</namePart><namePart type="family">Zaoui</namePart><affiliation>Faculté des Sciences, Université Chouaib doukkali, El‐Jadida, Morocco</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philippe</namePart><namePart type="family">Beaune</namePart><affiliation>Laboratoire Toxicologie Moléculaire, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Annie</namePart><namePart type="family">Pfohl‐Leszkowicz</namePart><affiliation>Laboratoire de Toxicologie et Sécurité Alimentaire, ENSAT, Auzeville‐Tolosane, France</affiliation><affiliation>ENSAT, Laboratoire de Toxicologie et Sécurité Alimentaire, avenue de l'Agrobiopole BP 107, F‐31326 Auzeville‐Tolosane, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>John Wiley & Sons, Inc.</publisher><place><placeTerm type="text">New York</placeTerm></place><dateIssued encoding="w3cdtf">2000</dateIssued><dateCaptured encoding="w3cdtf">1999-07-04</dateCaptured><dateValid encoding="w3cdtf">1999-11-01</dateValid><copyrightDate encoding="w3cdtf">2000</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">5</extent><extent unit="tables">2</extent><extent unit="references">59</extent><extent unit="words">6708</extent></physicalDescription><abstract lang="en">Ochratoxin A (OTA), a mycotoxin that induces nephrotoxicity and urinary tract tumors, is genotoxic and can be metabolized not only by different cytochromes P450 (CYP) but also by peroxidases involved in the arachidonic cascade, although the exact nature of the metabolites involved in the genotoxic process is still unknown. In order to establish the relation between OTA genotoxicity and the formation of metabolites, we chose three experimental models: kidney microsomes from rabbit, human bronchial epithelial cells, and microsomes from yeast that specifically express the human cytochrome P450 2C9 or 2B6 genes. OTA‐DNA adducts were analyzed by 32P postlabeling and the OTA derivatives formed were isolated by HPLC after incubation of OTA in the presence of: (1) kidney microsomes from rabbit pretreated or not with phenobarbital (PB); (2) human pulmonary epithelial cells simultaneously pretreated (or not) with PB alone or in the presence of ethacrynic acid (EA); (3) microsomes expressing CYP 2B6 and 2C9. PB pretreatment significantly increased DNA adducts formed after OTA treatment, both in the presence of kidney microsomes and bronchial epithelial cells, and induced the formation of new adducts. Ethacrynic acid, which inhibits microsomal glutathione‐S‐transferase, reduced DNA adduct level. DNA adducts were detected when OTA were incubated with microsomes expressing human CYP 2C9 but not with those expressing CYP 2B6. Several metabolites detected by HPLC were increased after PB treatment. Some of them could be related to DNA‐adduct formation. In conclusion, OTA biotransformation, enhanced by PB pretreatment, increased DNA‐adduct formation through pathways involving microsomal glutathion‐S‐transferase and CYP 2C9. Environ. Mol. Mutagen. 35:123–131, 2000 © 2000 Wiley‐Liss, Inc.</abstract><note type="funding">French Ministry of Research and Universities - No. Action Spécifique 97‐1477; No. DRED 1970; </note><note type="funding">Midi‐Pyrénées Region - No. 9408014; No. 9600487; No. 9609624; </note><subject lang="en"><genre>keywords</genre><topic>DNA adducts</topic><topic>ochratoxin A</topic><topic>human bronchial epithelial cells</topic><topic>kidney rabbit microsomes</topic><topic>human CYP 2C9</topic><topic>human CYP 2B6</topic><topic>microsomal glutathione‐S‐transferase</topic></subject><relatedItem type="host"><titleInfo><title>Environmental and Molecular Mutagenesis</title></titleInfo><titleInfo type="abbreviated"><title>Environ. Mol. 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