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Research ArticleArticle

Quantitative Profiling of Human Renal UDP-glucuronosyltransferases and Glucuronidation Activity: A Comparison of Normal and Tumoral Kidney Tissues

Guillaume Margaillan, Michèle Rouleau, John K. Fallon, Patrick Caron, Lyne Villeneuve, Véronique Turcotte, Philip C. Smith, Melanie S. Joy and Chantal Guillemette
Drug Metabolism and Disposition April 2015, 43 (4) 611-619; DOI: https://doi.org/10.1124/dmd.114.062877
Guillaume Margaillan
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Michèle Rouleau
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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John K. Fallon
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Patrick Caron
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Lyne Villeneuve
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Véronique Turcotte
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Philip C. Smith
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Melanie S. Joy
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Chantal Guillemette
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, and Faculty of Pharmacy, Laval University, Quebec, Canada (G.M., M.R., P.C., L.V., V.T., C.G.); Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.K.F., P.C.S.); and University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Boulder, Colorado (M.S.J.)
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Abstract

Renal metabolism by UDP-glucuronosyltransferase (UGT) enzymes is central to the clearance of many drugs. However, significant discrepancies about the relative abundance and activity of individual UGT enzymes in the normal kidney prevail among reports, whereas glucuronidation in tumoral kidney has not been examined. In this study, we performed an extensive profiling of glucuronidation metabolism in normal (n = 12) and tumor (n = 14) kidneys using targeted mass spectrometry quantification of human UGTs. We then correlated UGT protein concentrations with mRNA levels assessed by quantitative polymerase chain reaction and with conjugation activity for the major renal UGTs. Beyond the wide interindividual variability in expression levels observed among kidney samples, UGT1A9, UGT2B7, and UGT1A6 are the most abundant renal UGTs in both normal and tumoral tissues based on protein quantification. In normal kidney tissues, only UGT1A9 protein levels correlated with mRNA levels, whereas UGT1A6, UGT1A9, and UGT2B7 quantification correlated significantly with their mRNA levels in tumor kidneys. Data support that posttranscriptional regulation of UGT2B7 and UGT1A6 expression is modulating glucuronidation in the kidney. Importantly, our study reveals a significant decreased glucuronidation capacity of neoplastic kidneys versus normal kidneys that is paralleled by drastically reduced UGT1A9 and UGT2B7 mRNA and protein expression. UGT2B7 activity is the most repressed in tumors relative to normal tissues, with a 96-fold decrease in zidovudine metabolism, whereas propofol and sorafenib glucuronidation is decreased by 7.6- and 5.2-fold, respectively. Findings demonstrate that renal drug metabolism is predominantly mediated by UGT1A9 and UGT2B7 and is greatly reduced in kidney tumors.

Footnotes

    • Received December 19, 2014.
    • Accepted February 3, 2015.
  • This work was supported by the Canadian Institutes of Health Research (CIHR) [MOP-42392]; the Natural the Sciences and Engineering Research Council of Canada [CG086976]; the Canada Research Chair in Pharmacogenomics (Tier I); the Fonds d’enseignement et de recherche, Laval University (graduate scholarship); and supported in part by the National Institutes of Health Division of Research Resources [Instrumentation Grant S10-RR024595].

  • dx.doi.org/10.1124/dmd.114.062877.

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

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (4)
Drug Metabolism and Disposition
Vol. 43, Issue 4
1 Apr 2015
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Research ArticleArticle

Renal Glucuronidation by Normal and Tumoral Tissues

Guillaume Margaillan, Michèle Rouleau, John K. Fallon, Patrick Caron, Lyne Villeneuve, Véronique Turcotte, Philip C. Smith, Melanie S. Joy and Chantal Guillemette
Drug Metabolism and Disposition April 1, 2015, 43 (4) 611-619; DOI: https://doi.org/10.1124/dmd.114.062877

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Research ArticleArticle

Renal Glucuronidation by Normal and Tumoral Tissues

Guillaume Margaillan, Michèle Rouleau, John K. Fallon, Patrick Caron, Lyne Villeneuve, Véronique Turcotte, Philip C. Smith, Melanie S. Joy and Chantal Guillemette
Drug Metabolism and Disposition April 1, 2015, 43 (4) 611-619; DOI: https://doi.org/10.1124/dmd.114.062877
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