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: Guillaume Margaillan, Michèle Rouleau, John K Fallon, Patrick Caron, Lyne Villeneuve, Véronique Turcotte, Philip C Smith, Melanie S Joy, Chantal Guillemette
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 43 Issue 4 Pg. 611-9 (Apr 2015) ISSN: 1521-009X [Electronic] United States
• PMID: 25650382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Glucuronides
• Pharmaceutical Preparations
• RNA, Messenger
• UGT1A9 protein, human
• UDP-glucuronosyltransferase, UGT1A6
• UGT2B7 protein, human
• Glucuronosyltransferase
• UDP-Glucuronosyltransferase 1A9

Topics

• Carcinoma, Renal Cell (enzymology, metabolism, pathology)
• Glucuronides (metabolism)
• Glucuronosyltransferase (genetics, metabolism)
• Humans
• Kidney (enzymology, metabolism, pathology)
• Kidney Neoplasms (enzymology, metabolism, pathology)
• Pharmaceutical Preparations (metabolism)
• RNA, Messenger (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• UDP-Glucuronosyltransferase 1A9