Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate
Identifieur interne : 002117 ( Istex/Corpus ); précédent : 002116; suivant : 002118Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate
Auteurs : J. Trottier ; M. Perreault ; I. Rudkowska ; C. Levy ; A. Dallaire-Theroux ; M. Verreault ; P. Caron ; B. Staels ; M-C Vohl ; R J Straka ; O. BarbierSource :
- Clinical Pharmacology & Therapeutics [ 0009-9236 ] ; 2013-10.
Abstract
Glucuronidation, catalyzed by uridine 5′‐diphospho‐glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA‐glucuronide (BA‐G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid‐lowering drug fenofibrate on the circulating BA‐G profile in 300 volunteers and 5 cholestatic patients. Eleven BA‐Gs were determined in pre‐ and postfenofibrate samples. Men exhibited higher BA‐G concentrations, and various genotype/BA‐G associations were discovered in relevant UGT genes. The chenodeoxycholic acid‐3G (CDCA‐3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA‐3G formation. Fenofibrate exposure increased the serum levels of five BA‐G species, including CDCA‐3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.
Url:
DOI: 10.1038/clpt.2013.122
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Barbier</name><affiliation><mods:affiliation>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Clinical Pharmacology & Therapeutics</title><title level="j" type="abbrev">Clinical Pharmacology & Therapeutics</title><idno type="ISSN">0009-9236</idno><idno type="eISSN">1532-6535</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2013-10">2013-10</date><biblScope unit="volume">94</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="533">533</biblScope><biblScope unit="page" to="543">543</biblScope></imprint><idno type="ISSN">0009-9236</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0009-9236</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Glucuronidation, catalyzed by uridine 5′‐diphospho‐glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA‐glucuronide (BA‐G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid‐lowering drug fenofibrate on the circulating BA‐G profile in 300 volunteers and 5 cholestatic patients. Eleven BA‐Gs were determined in pre‐ and postfenofibrate samples. Men exhibited higher BA‐G concentrations, and various genotype/BA‐G associations were discovered in relevant UGT genes. The chenodeoxycholic acid‐3G (CDCA‐3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA‐3G formation. Fenofibrate exposure increased the serum levels of five BA‐G species, including CDCA‐3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>J Trottier</name><affiliations><json:string>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</json:string></affiliations></json:item><json:item><name>M Perreault</name><affiliations><json:string>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</json:string></affiliations></json:item><json:item><name>I Rudkowska</name><affiliations><json:string>Nutraceuticals and Functional Foods Institute and Endocrinology and Nephrology, CHU‐Québec Research Centre, Québec, Québec, Canada</json:string></affiliations></json:item><json:item><name>C 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This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.</p></abstract><abstract><p>Clinical Pharmacology & Therapeutics (2013); 94 4, 533–543. doi:10.1038/clpt.2013.122</p></abstract><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2013-02-07">Received</change><change when="2013-05-31">Registration</change><change when="2014-11-28">Created</change><change when="2013-10">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/F8259C75FAB3F8DEB95E4B44580A6E5BF54853AA/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" 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corresponding="no"><personName><givenNames>M</givenNames><familyName>Perreault</familyName></personName></creator><creator xml:id="cptclpt2013122-cr-0003" creatorRole="author" affiliationRef="#cptclpt2013122-aff-0002" corresponding="no"><personName><givenNames>I</givenNames><familyName>Rudkowska</familyName></personName></creator><creator xml:id="cptclpt2013122-cr-0004" creatorRole="author" affiliationRef="#cptclpt2013122-aff-0003" corresponding="no"><personName><givenNames>C</givenNames><familyName>Levy</familyName></personName></creator><creator xml:id="cptclpt2013122-cr-0005" creatorRole="author" affiliationRef="#cptclpt2013122-aff-0001" corresponding="no"><personName><givenNames>A</givenNames><familyName>Dallaire‐Theroux</familyName></personName></creator><creator xml:id="cptclpt2013122-cr-0006" creatorRole="author" affiliationRef="#cptclpt2013122-aff-0001" corresponding="no"><personName><givenNames>M</givenNames><familyName>Verreault</familyName></personName></creator><creator 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corresponding="yes"><personName><givenNames>O</givenNames><familyName>Barbier</familyName></personName><contactDetails><email>olivier.barbier@crchul.ulaval.ca</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="cptclpt2013122-aff-0001" type="organization" countryCode="CA"><orgDiv>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy</orgDiv><orgName>Laval University</orgName><address><city>Quebec City</city><countryPart>Québec</countryPart><country>Canada</country></address></affiliation><affiliation xml:id="cptclpt2013122-aff-0002" type="organization" countryCode="CA"><orgDiv>Nutraceuticals and Functional Foods Institute and Endocrinology and Nephrology</orgDiv><orgName>CHU‐Québec Research Centre, Québec</orgName><address><countryPart>Québec</countryPart><country>Canada</country></address></affiliation><affiliation xml:id="cptclpt2013122-aff-0003" type="organization" countryCode="US"><orgDiv>Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine</orgDiv><orgName>University of Florida</orgName><address><city>Gainesville</city><countryPart>Florida</countryPart><country>USA</country></address></affiliation><affiliation xml:id="cptclpt2013122-aff-0004" type="organization" countryCode="FR"><orgDiv>INSERM‐U1011</orgDiv><orgName>Institut Pasteur de Lille and Université Lille</orgName><address><countryPart>Lille</countryPart><country>France</country></address></affiliation><affiliation xml:id="cptclpt2013122-aff-0005" type="organization" countryCode="US"><orgDiv>Department of Experimental and Clinical Pharmacology, College of Pharmacy</orgDiv><orgName>University of Minnesota</orgName><address><city>Minneapolis</city><countryPart>Minnesota</countryPart><country>USA</country></address></affiliation></affiliationGroup><supportingInformation><supportingInfoItem xml:id="cptclpt2013122-sup-0001"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0001"></mediaResource><caption>Supplementary Information S1</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0002"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0002"></mediaResource><caption>Supplementary Information S2</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0003"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0003"></mediaResource><caption>Supplementary Information S3</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0004"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0004"></mediaResource><caption>Supplementary Information S4</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0005"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0005"></mediaResource><caption>Supplementary Information S5</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0006"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0006"></mediaResource><caption>Supplementary Information S6</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0007"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0007"></mediaResource><caption>Supplementary Information S7</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0008"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0008"></mediaResource><caption>Supplementary Information S8</caption></supportingInfoItem><supportingInfoItem xml:id="cptclpt2013122-sup-0009"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:00099236:media:cptclpt2013122:cptclpt2013122-sup-0009"></mediaResource><caption>Supplementary Information S9</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main"><p>Glucuronidation, catalyzed by uridine 5′‐diphospho‐glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA‐glucuronide (BA‐G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid‐lowering drug fenofibrate on the circulating BA‐G profile in 300 volunteers and 5 cholestatic patients. Eleven BA‐Gs were determined in pre‐ and postfenofibrate samples. Men exhibited higher BA‐G concentrations, and various genotype/BA‐G associations were discovered in relevant UGT genes. The chenodeoxycholic acid‐3G (CDCA‐3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA‐3G formation. Fenofibrate exposure increased the serum levels of five BA‐G species, including CDCA‐3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.</p><p><i>Clinical Pharmacology & Therapeutics</i> (2013); <b>94</b> 4, 533–543. doi:<accessionId ref="info:doi/10.1038/clpt.2013.122">10.1038/clpt.2013.122</accessionId></p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Trottier</namePart><affiliation>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Perreault</namePart><affiliation>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">I</namePart><namePart type="family">Rudkowska</namePart><affiliation>Nutraceuticals and Functional Foods Institute and Endocrinology and Nephrology, CHU‐Québec Research Centre, Québec, Québec, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Levy</namePart><affiliation>Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Florida, Florida, Gainesville, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Dallaire‐Theroux</namePart><affiliation>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Verreault</namePart><affiliation>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Caron</namePart><affiliation>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">B</namePart><namePart type="family">Staels</namePart><affiliation>INSERM‐U1011, Institut Pasteur de Lille and Université Lille, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M‐C</namePart><namePart type="family">Vohl</namePart><affiliation>Nutraceuticals and Functional Foods Institute and Endocrinology and Nephrology, CHU‐Québec Research Centre, Québec, Québec, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">R J</namePart><namePart type="family">Straka</namePart><affiliation>Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minnesota, Minneapolis, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">O</namePart><namePart type="family">Barbier</namePart><affiliation>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2013-10</dateIssued><dateCreated encoding="w3cdtf">2014-11-28</dateCreated><dateCaptured encoding="w3cdtf">2013-02-07</dateCaptured><dateValid encoding="w3cdtf">2013-05-31</dateValid><copyrightDate encoding="w3cdtf">2013</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Glucuronidation, catalyzed by uridine 5′‐diphospho‐glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA‐glucuronide (BA‐G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid‐lowering drug fenofibrate on the circulating BA‐G profile in 300 volunteers and 5 cholestatic patients. Eleven BA‐Gs were determined in pre‐ and postfenofibrate samples. Men exhibited higher BA‐G concentrations, and various genotype/BA‐G associations were discovered in relevant UGT genes. The chenodeoxycholic acid‐3G (CDCA‐3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA‐3G formation. Fenofibrate exposure increased the serum levels of five BA‐G species, including CDCA‐3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.</abstract><abstract>Clinical Pharmacology & Therapeutics (2013); 94 4, 533–543. doi:10.1038/clpt.2013.122</abstract><note type="additional physical form">Supplementary Information S1Supplementary Information S2Supplementary Information S3Supplementary Information S4Supplementary Information S5Supplementary Information S6Supplementary Information S7Supplementary Information S8Supplementary Information S9</note><relatedItem type="host"><titleInfo><title>Clinical Pharmacology & Therapeutics</title></titleInfo><titleInfo type="abbreviated"><title>Clinical Pharmacology & Therapeutics</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>Article</topic></subject><identifier type="ISSN">0009-9236</identifier><identifier type="eISSN">1532-6535</identifier><identifier type="DOI">10.1002/(ISSN)1532-6535</identifier><identifier type="PublisherID">CPT</identifier><part><date>2013</date><detail type="title"><title>Heart Failure</title></detail><detail type="volume"><caption>vol.</caption><number>94</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>533</start><end>543</end><total>11</total></extent></part></relatedItem><identifier type="istex">F8259C75FAB3F8DEB95E4B44580A6E5BF54853AA</identifier><identifier type="DOI">10.1038/clpt.2013.122</identifier><identifier type="ArticleID">CPTCLPT2013122</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2013 American Society for Clinical Pharmacology and Therapeutics© 2013 American Society for Clinical Pharmacology and Therapeutics</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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