A pharmacogenetics study of the human glucuronosyltransferase UGT1A4

DC FieldValueLanguage
dc.contributor.authorBenoît-Biancamano, Marie-Odile-
dc.contributor.authorAdam, Jean-Philippe-
dc.contributor.authorBernard, Olivier-
dc.contributor.authorCourt, Michael H.-
dc.contributor.authorLeblanc, Marie-Hélène-
dc.contributor.authorCaron, Patrick-
dc.contributor.authorGuillemette, Chantal-
dc.date.accessioned2016-09-30T13:20:15Z-
dc.date.available2016-09-30T13:20:15Z-
dc.date.issued2009-12-01-
dc.identifier.issn1744-6872fr_CA
dc.identifier.urihttp://hdl.handle.net/20.500.11794/10669-
dc.description.abstractUGT1A4 is primarily expressed in the liver and exhibits catalytic activities for various drugs. Amongst the few UGT1A4 polymorphisms evaluated, studies support the alteration of UGT1A4-mediated glucuronidation by a few variations including the Pro24Thr and Leu48Val variants (referred to as UGT1A4*2 and *3). We therefore investigated genetic mechanisms that might contribute to interindividual variation in UGT1A4 expression and activity. The UGT1A4 gene was sequenced from -4963 bp relative to the ATG to 2000 bp after the first exon in 184 unrelated Caucasians and African-Americans. We identified a large number of genetic variations, including 13 intronic, 39 promoter, as well as 14 exonic polymorphisms, with 10 that lead to aminoacid changes. Of the nucleotide variations found in the -5kb promoter region, 5 are located in the proximal region (first 500 bp), and positioned in putative HNF-1 and OCT- 1 binding sites. Four of these variants, placed at -163, -219, -419 and -463, are in complete linkage disequilibrium with the Leu48Val coding region variant and with several variants in the upstream region of the promoter. Transient transfections of reference and variant promoter constructs (from position -500 to +1) in different cell lines with or without co-expression of HNF-1 and/or OCT-1, demonstrated limited effect of these variations. However, several coding variants significantly modified the enzyme kinetics for tamoxifen and Z-4-hydroxytamoxifen (Val48, Asp50, Gln56, Phe176, Asn250, Leu276). Our results reveal that, despite a large number of polymorphisms located in the promoter region, the exonic variants are those expected to have a potential in vivo effect.fr_CA
dc.languageengfr_CA
dc.publisherLippincott Williams & Wilkinsfr_CA
dc.subjectPharmacogeneticsfr_CA
dc.subjectPolymorphismsfr_CA
dc.subjectTamoxifenfr_CA
dc.subjectUGTfr_CA
dc.titleA pharmacogenetics study of the human glucuronosyltransferase UGT1A4fr_CA
dc.typeCOAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherche-
dcterms.bibliographicCitationPharmacogenetics and genomics, Vol. 19 (12), 945–954 (2009)fr_CA
dc.audiencePharmaciensfr_CA
dc.audienceProfesseurs (Enseignement supérieur)fr_CA
dc.audienceÉtudiantsfr_CA
dc.audienceDoctorantsfr_CA
dc.identifier.doi10.1097/FPC.0b013e3283331637fr_CA
dc.identifier.pubmed19890225fr_CA
dc.subject.rvmGlucuronosyltransférasefr_CA
dc.subject.rvmPharmacogénétiquefr_CA
dc.subject.rvmPolymorphisme génétiquefr_CA
dc.subject.rvmTamoxifènefr_CA
rioxxterms.versionAccepted Manuscriptfr_CA
rioxxterms.version_of_recordhttps://doi.org/10.1097/FPC.0b013e3283331637fr_CA
rioxxterms.projectMOP-42392fr_CA
rioxxterms.project.funder_nameCanadian Institutes of Health Researchfr_CA
bul.rights.periodeEmbargo12 moisfr_CA
Collection:Articles publiés dans des revues avec comité de lecture

Files in this item:
Description SizeFormat 
UGT1A4 PGx 12-06-2009.pdf612.63 kBAdobe PDFThumbnail
View/Open
All documents in CorpusUL are protected by Copyright Act of Canada.