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Research ArticleArticle

Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody

Jean-Philippe Émond, Adrien Labriet, Sylvie Desjardins, Michèle Rouleau, Lyne Villeneuve, Hélène Hovington, Hervé Brisson, Louis Lacombe, David Simonyan, Patrick Caron, Martine Périgny, Bernard Têtu, John K. Fallon, Kathrin Klein, Philip C. Smith, Ulrich M. Zanger, Chantal Guillemette and Eric Lévesque
Drug Metabolism and Disposition May 2019, 47 (5) 444-452; DOI: https://doi.org/10.1124/dmd.119.086330
Jean-Philippe Émond
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Adrien Labriet
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Sylvie Desjardins
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Michèle Rouleau
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Lyne Villeneuve
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Hélène Hovington
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Hervé Brisson
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Louis Lacombe
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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David Simonyan
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Patrick Caron
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Martine Périgny
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Bernard Têtu
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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John K. Fallon
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Kathrin Klein
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Philip C. Smith
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Ulrich M. Zanger
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Chantal Guillemette
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Eric Lévesque
Centre Hospitalier Universitaire (CHU) de Québec Research Centre and Faculty of Medicine (J.-P.É., S.D., H.H., H.B., L.L., M.P., B.T., E.L.) and CHU de Québec Research Centre and Faculty of Pharmacy, Laval University (A.L., M.R., L.V., P.C., C.G.), and Statistical and Clinical Research Platform, CHU de Québec Research Centre (D.S.), Québec, Canada.); Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (K.K., U.M.Z.)
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Abstract

Accurate quantification of the metabolic enzyme uridine diphospho-glucuronosyltransferase (UGT) 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 revealed 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, located in the binding site for the transcription factor forkhead box A1 (FOXA1) of the UGT2B17 promoter. The highest level of expression was observed for individuals carrying at least one rs59678213 A allele. Multiple regression analysis indicated that the number of gene copies explained only 8% of UGT2B17 protein expression, 49% when adding rs59678213, reaching 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 the UGT2B17 level in various disease states and establish more precisely the contribution of the UGT2B17 enzyme to drug and hormone metabolism.

Footnotes

    • Received January 9, 2019.
    • Accepted February 21, 2019.
  • This research was funded by the CHU de Québec (to E.L.) by the Canadian Institutes of Health Research (FRN-42392 and FRN-152986). E.L. is recipient of the CIHR phase 2 clinician-scientist award. C.G. holds a Canada Research Chair in Pharmacogenomics. A.L. receives graduate scholarships from the Fonds d’enseignement et de recherche of the Faculty of Pharmacy and the Fonds de Recherche du Québec—Santé.

  • https://doi.org/10.1124/dmd.119.086330.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 47 (5)
Drug Metabolism and Disposition
Vol. 47, Issue 5
1 May 2019
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Research ArticleArticle

Specific Quantification of UGT2B17

Jean-Philippe Émond, Adrien Labriet, Sylvie Desjardins, Michèle Rouleau, Lyne Villeneuve, Hélène Hovington, Hervé Brisson, Louis Lacombe, David Simonyan, Patrick Caron, Martine Périgny, Bernard Têtu, John K. Fallon, Kathrin Klein, Philip C. Smith, Ulrich M. Zanger, Chantal Guillemette and Eric Lévesque
Drug Metabolism and Disposition May 1, 2019, 47 (5) 444-452; DOI: https://doi.org/10.1124/dmd.119.086330

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Research ArticleArticle

Specific Quantification of UGT2B17

Jean-Philippe Émond, Adrien Labriet, Sylvie Desjardins, Michèle Rouleau, Lyne Villeneuve, Hélène Hovington, Hervé Brisson, Louis Lacombe, David Simonyan, Patrick Caron, Martine Périgny, Bernard Têtu, John K. Fallon, Kathrin Klein, Philip C. Smith, Ulrich M. Zanger, Chantal Guillemette and Eric Lévesque
Drug Metabolism and Disposition May 1, 2019, 47 (5) 444-452; DOI: https://doi.org/10.1124/dmd.119.086330
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