Posttranscriptional regulation of UGT2B10 hepatic expression and activity by alternative splicing

Auteur(s): Labriet, AdrienGuillemette, ChantalAudet-Delage, YannickVilleneuve, LyneAllain, EricRouleau, Michèle
Résumé: The 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 activity.
Type de document: Article de recherche
Date de publication: 9 février 2018
Date de la mise en libre accès: 16 mai 2018
Version du document: VoR
Lien permanent: http://hdl.handle.net/20.500.11794/16775
Ce document a été publié dans: Drug metabolism and disposition, (2018)
https://doi.org/10.1124/dmd.117.079921
American Society for Pharmacology and Experimental Therapeutics
Autre version disponible: 10.1124/dmd.117.079921
29438977
Collection :Articles publiés dans des revues avec comité de lecture

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