Factors affecting interindividual variability of hepatic UGT2B17 protein expression examined using a novel specific monoclonal antibody

Authors: Emond, Jean-PhilippeLabriet, AdrienDesjardins, SylvieRouleau, MichèleVilleneuve, LyneHovington, HélèneBrisson, HervéLacombe, LouisSimonyan, DavidCaron, PatrickPérigny, MartineTêtu, Bernard; Fallon, John K.; Klein, Kathrin; Smith, Philip; Zanger, Ulrich M.; Guillemette, ChantalLévesque, Éric
Abstract: The accurate quantification of the metabolic enzyme UGT2B17 has been hampered by the high sequence identity with other UGT2B enzymes (as high as 94%) and by the lack of a specific antibody. Knowing the significance of the UGT2B17 pathway in drug and hormone metabolism and cancer, we developed a specific monoclonal antibody (EL-2B17mAb), initially validated by the lack of detection in liver microsomes of an individual carrying no UGT2B17 gene copy and in supersomes expressing UGT2B enzymes. Immunohistochemical detection in livers reveals a strong labeling of bile ducts and variable labeling of hepatocytes. Expression levels assessed by immunoblotting were highly correlated to mass spectrometry-based quantification (r = 0.93) and three major expression patterns (absent, low or high) were evidenced. Livers with very low expression were carriers of the functional rs59678213 G variant, which is located in the binding site for the transcription factor Forkhead Box A1 (FOXA1) of the UGT2B17 promoter. The highest expression was observed for individuals carrying at least one rs59678213 A allele. A multiple regression analysis indicated that the number of gene copies explained only 8% of UGT2B17 protein expression, 49% when adding rs59678213 and reached 54% when including sex. The novel EL-2B17mAb antibody allowed specific UGT2B17 quantification and exposed different patterns of hepatic expression. It further suggests that FOXA1 is a key driver of UGT2B17 expression in the liver. The availability of this molecular tool will help characterize UGT2B17 level in various disease states and establish more precisely the UGT2B17 enzyme contribution to drug and hormone metabolism
Document Type: Article de recherche
Issue Date: 28 February 2019
Open Access Date: Restricted access
Document version: AM
Permalink: http://hdl.handle.net/20.500.11794/33995
This document was published in: Drug Metabolism and Dispositio, Vol. 47, (4), 1-35 (2019)
https://doi.org/10.1124/dmd.119.086330
American Society for Pharmacology and Experimental Therapeutics, etc.
Alternative version: 10.1124/dmd.119.086330
Collection:Articles publiés dans des revues avec comité de lecture

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