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Immunohistochemical expression of conjugating UGT1A-derived splice proteins in normal and tumoral drug-metabolising tissues in humans

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bul.description.provenancedvafr_CA
bul.description.provenancespbfr_CA
bul.rights.dateAccepPubl2010-10-29fr_CA
bul.rights.periodeEmbargoP0Mfr_CA
bul.rights.typeDatedatePublicationfr_CA
dc.audienceBiochimistesfr_CA
dc.audienceProfesseurs (Enseignement supérieur)fr_CA
dc.audienceÉtudiantsfr_CA
dc.audienceDoctorantsfr_CA
dc.contributor.authorBellemare, Judith.
dc.contributor.authorPelletier, Georges
dc.contributor.authorPopa, Ion
dc.contributor.authorTêtu, Bernard
dc.contributor.authorHarvey, Mario.
dc.contributor.authorGuillemette, Chantal
dc.contributor.authorRouleau, Mélanie
dc.date.accessioned2016-09-01T13:03:50Z
dc.date.available2016-09-01T13:03:50Z
dc.date.issued2010-10-29
dc.description.abstractGlucuronidation by UDP-glucuronyltransferase (UGT) enzymes is the prevailing conjugative pathway for the metabolism of both xenobiotics and endogenous compounds. Alterations in this pathway, such as those generated by common genetic polymorphisms, have been shown to significantly impact on the health of individuals, influencing cancer susceptibility, responsiveness to drugs and drug-induced toxicity. Alternative usage of terminal exons leads to UGT1A-derived splice variants, namely the classical and enzymatically active isoforms 1 (i1) and the novel enzymatically inactive isoforms 2 (i2). In vitro functional data from heterologous expression and RNA interference experiments indicate that these i2 isoforms act as negative modulators of glucuronidation, likely by forming inactive complexes with active isoform 1. We used specific antibodies against either active i1 or inactive i2 proteins to examine their distribution in major drug-metabolizing tissues. Data revealed that UGT1A_i1 and inactive UGT1A_i2 are co-produced in the same tissue structures, including liver, kidney, stomach, intestine and colon. Examination of the cellular distribution and semi-quantitative level of expression of UGT1As revealed heterogeneous expression of i1 and i2 proteins, with increased expression of i2 in liver tumours and decreased levels of i1 and i2 in colon cancer specimens, compared to normal tissues. These differences in expression may be relevant to human colon and liver cancer tumorigenesis. Our data clearly demonstrate the similar immunolocalization of active and inactive UGT1A isoforms in most UGT1A-expressing cell types of major tissues involved in drug metabolism. These expression patterns are consistent with a dominant-negative function for the i2 encoded by the UGT1A gene.fr_CA
dc.identifier.doi10.1002/path.2805fr_CA
dc.identifier.issn0022-3417fr_CA
dc.identifier.pubmed21171088fr_CA
dc.identifier.urihttp://hdl.handle.net/20.500.11794/9608
dc.languageengfr_CA
dc.publisherWileyfr_CA
dc.rightshttp://purl.org/coar/access_right/c_abf2
dc.subjectUDP-glucuronosyltransferase (UGT)fr_CA
dc.subjectSplice variantsfr_CA
dc.subjectDominant negative functionfr_CA
dc.subjectHuman tissuesfr_CA
dc.subjectMetabolismfr_CA
dc.subject.rvmImmunocytochimiefr_CA
dc.subject.rvmGlucuronosyltransférasefr_CA
dc.subject.rvmTissus (Histologie)fr_CA
dc.subject.rvmMédicaments -- Métabolismefr_CA
dc.subject.rvmÉpissagefr_CA
dc.subject.rvmProtéinesfr_CA
dc.titleImmunohistochemical expression of conjugating UGT1A-derived splice proteins in normal and tumoral drug-metabolising tissues in humansfr_CA
dc.typearticle de recherche
dc.type.legacyCOAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherche
dcterms.bibliographicCitationThe Journal of pathology, Vol. 223 (3), 425-435 (2011)fr_CA
dspace.accessstatus.time2023-05-25 18:19:22
dspace.entity.typePublication
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rioxxterms.project84223/111086fr_CA
rioxxterms.project.funder-nameCanadian Institutes of Health Researchfr_CA
rioxxterms.versionAccepted Manuscript (AM)fr_CA
rioxxterms.version-of-recordhttps://doi.org/10.1002/path.2805fr_CA
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