Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate
Identifieur interne : 000107 ( France/Analysis ); précédent : 000106; suivant : 000108Profiling Serum Bile Acid Glucuronides in Humans: Gender Divergences, Genetic Determinants, and Response to Fenofibrate
Auteurs : J. Trottier [Canada] ; M. Perreault [Canada] ; I. Rudkowska [Canada] ; C. Levy [États-Unis] ; A. Dallaire-Theroux [Canada] ; M. Verreault [Canada] ; P. Caron [Canada] ; B. Staels [France] ; M-C Vohl [Canada] ; R J Straka [États-Unis] ; O. Barbier [Canada]Source :
- 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
Affiliations:
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Barbier</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Laboratory of Molecular Pharmacology, Endocrinology, and Nephrology, CHU‐Québec Research Centre and the Faculty of Pharmacy, Laval University, Québec, Quebec City</wicri:regionArea><wicri:noRegion>Quebec City</wicri:noRegion></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><affiliations><list><country><li>Canada</li><li>France</li><li>États-Unis</li></country><region><li>Hauts-de-France</li><li>Nord-Pas-de-Calais</li></region><settlement><li>Lille</li></settlement></list><tree><country name="Canada"><noRegion><name sortKey="Trottier, J" sort="Trottier, J" uniqKey="Trottier J" first="J" last="Trottier">J. Trottier</name></noRegion><name sortKey="Barbier, O" sort="Barbier, O" uniqKey="Barbier O" first="O" last="Barbier">O. Barbier</name><name sortKey="Caron, P" sort="Caron, P" uniqKey="Caron P" first="P" last="Caron">P. Caron</name><name sortKey="Dallaire Heroux, A" sort="Dallaire Heroux, A" uniqKey="Dallaire Heroux A" first="A" last="Dallaire-Theroux">A. Dallaire-Theroux</name><name sortKey="Perreault, M" sort="Perreault, M" uniqKey="Perreault M" first="M" last="Perreault">M. Perreault</name><name sortKey="Rudkowska, I" sort="Rudkowska, I" uniqKey="Rudkowska I" first="I" last="Rudkowska">I. Rudkowska</name><name sortKey="Verreault, M" sort="Verreault, M" uniqKey="Verreault M" first="M" last="Verreault">M. Verreault</name><name sortKey="Vohl, M" sort="Vohl, M" uniqKey="Vohl M" first="M-C" last="Vohl">M-C Vohl</name></country><country name="États-Unis"><noRegion><name sortKey="Levy, C" sort="Levy, C" uniqKey="Levy C" first="C" last="Levy">C. Levy</name></noRegion><name sortKey="Straka, R J" sort="Straka, R J" uniqKey="Straka R" first="R J" last="Straka">R J Straka</name></country><country name="France"><region name="Hauts-de-France"><name sortKey="Staels, B" sort="Staels, B" uniqKey="Staels B" first="B" last="Staels">B. Staels</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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