Posttranscriptional regulation of UGT2B10 hepatic expression and activity by alternative splicing

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dc.contributor.authorLabriet, Adrien-
dc.contributor.authorGuillemette, Chantal-
dc.contributor.authorAudet-Delage, Yannick-
dc.contributor.authorVilleneuve, Lyne-
dc.contributor.authorAllain, Eric-
dc.contributor.authorRouleau, Michèle-
dc.description.abstractThe detoxification enzyme UDP-glucuronosyltransferase UGT2B10 is specialized in the N-linked glucuronidation of many drugs and xenobiotics. Preferred substrates possess tertiary aliphatic amines and heterocyclic amines such as tobacco carcinogens and several anti-depressants and anti-psychotics. We hypothesized that alternative splicing (AS) constitutes a mean to regulate steady state levels of UGT2B10 and enzyme activity. We established the transcriptome of UGT2B10 in normal and tumoral tissues of multiple individuals. Highest expression was in the liver, where ten AS transcripts represented 50% of the UGT2B10 transcriptome in 50 normal livers and 44 hepatocellular carcinomas. One abundant class of transcripts involves a novel exonic sequence and leads to two alternative (alt.) variants with novel in-frame C-termini of 10 or 65 amino acids. Their hepatic expression was highly variable among individuals, correlated with canonical transcript levels, and was 3.5 fold higher in tumors. Evidence for their translation in liver tissues was acquired by mass spectrometry. In cell models, they co-localized with the enzyme and influenced the conjugation of amitriptyline and levomedetomidine by repressing or activating the enzyme (40-70%; P<0.01), in a cell context-specific manner. A high turnover rate for the alt. proteins, regulated by the proteasome, was observed in contrast to the more stable UGT2B10 enzyme. Moreover, a drug-induced remodelling of UGT2B10 splicing was demonstrated in the HepaRG hepatic cell model, which favored alt. variants expression over the canonical transcript. Our findings support a significant contribution of AS in the regulation of UGT2B10 expression in the liver with an impact on enzyme
dc.publisherAmerican Society for Pharmacology and Experimental Therapeuticsfr
dc.titlePosttranscriptional regulation of UGT2B10 hepatic expression and activity by alternative splicingfr
dc.typeCOAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherchefr
dcterms.bibliographicCitationDrug metabolism and disposition, (2018)fr
dc.subject.rvmÉpissage alternatiffr
dc.subject.rvmTranscription génétique -- Régulationfr
rioxxterms.versionVersion of Recordfr
rioxxterms.project.funder_nameCanadian Institutes of Health Researchfr
rioxxterms.project.funder_nameCanada Research Chair in Pharmacogenomicsfr
rioxxterms.project.funder_nameFonds d’enseignement et de recherchefr
rioxxterms.project.funder_nameFonds de Recherche du Québec - Santéfr
rioxxterms.project.funder_nameNational Cancer Institutefr
rioxxterms.project.funder_nameNational Human Genome Research Institutefr
rioxxterms.project.funder_nameNational Heart, Lung, and Blood Institutefr
rioxxterms.project.funder_nameNational Institute on Drug Abusefr
rioxxterms.project.funder_nameNational Institute of Mental Healthfr
rioxxterms.project.funder_nameNational Institute of Neurological Disorders and Strokefr
rioxxterms.project.funder_nameCancer Genome Atlasfr
Collection:Articles publiés dans des revues avec comité de lecture

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