title: Quantitative profiling of human renal UDP-glucuronosyltransferases and glucuronidation activity: a comparison of normal and tumoral kidney tissues.
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.
authors: 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.).
authors: Guillaume
authors: G
authors: Margaillan
authors: 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.).
authors: Michèle
authors: M
authors: Rouleau
authors: 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.).
authors: John K
authors: JK
authors: Fallon
authors: 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.).
authors: Patrick
authors: P
authors: Caron
authors: 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.).
authors: Lyne
authors: L
authors: Villeneuve
authors: 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.).
authors: Véronique
authors: V
authors: Turcotte
authors: 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.).
authors: Philip C
authors: PC
authors: Smith
authors: 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.).
authors: Melanie S
authors: MS
authors: Joy
authors: 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.) chantal.guillemette@crchudequebec.ulaval.ca.
authors: Chantal
authors: C
authors: Guillemette
mesh_terms: D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D020719:Glucuronides; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; C000715591:UGT1A9 protein, human; C110655:UDP-glucuronosyltransferase, UGT1A6; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9
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