Margaillan Guillaume, Rouleau Michèle, Fallon John K, Caron Patrick, Villeneuve Lyne, Turcotte Véronique, Smith Philip C, Joy Melanie S, Guillemette Chantal
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.).
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.)
Drug Metab Dispos. 2015 Apr;43(4):611-9. doi: 10.1124/dmd.114.062877. Epub 2015 Feb 3.
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.
尿苷二磷酸葡萄糖醛酸基转移酶（UGT）介导的肾脏代谢是许多药物清除的关键环节。然而，关于正常肾脏中各UGT酶的相对丰度和活性，不同报告之间存在显著差异，而肿瘤肾脏中的葡萄糖醛酸化作用尚未得到研究。在本研究中，我们通过靶向质谱法定量检测人UGT，对12例正常肾脏和14例肿瘤肾脏中的葡萄糖醛酸化代谢进行了广泛分析。然后，我们将UGT蛋白浓度与通过定量聚合酶链反应评估的mRNA水平以及主要肾脏UGT的结合活性进行了关联分析。除了肾脏样本中观察到的个体间表达水平存在广泛差异外，基于蛋白质定量分析，UGT1A9、UGT2B7和UGT1A6是正常和肿瘤组织中含量最丰富的肾脏UGT。在正常肾脏组织中，只有UGT1A9蛋白水平与mRNA水平相关，而在肿瘤肾脏中，UGT1A6、UGT1A9和UGT2B7的定量与它们的mRNA水平显著相关。数据支持UGT2B7和UGT1A6表达的转录后调控正在调节肾脏中的葡萄糖醛酸化作用。重要的是，我们的研究揭示，与正常肾脏相比，肿瘤肾脏的葡萄糖醛酸化能力显著降低，同时UGT1A9和UGT2B7的mRNA及蛋白表达也大幅减少。相对于正常组织，UGT2B7的活性在肿瘤中受到的抑制最为明显，齐多夫定代谢降低了96倍，而丙泊酚和索拉非尼的葡萄糖醛酸化分别降低了7.6倍和5.2倍。研究结果表明，肾脏药物代谢主要由UGT1A9和UGT2B7介导，且在肾肿瘤中大幅降低。
