BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 卷:1832 |
Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration | |
Article | |
Mutsaers, H. A. M.1,2  Wilmer, M. J. G.1  Reijnders, D.1  Jansen, J.2  van den Broek, P. H. H.1  Forkink, M.3  Schepers, E.5  Glorieux, G.5  Vanholder, R.5  van den Heuvel, L. P.4,6  Hoenderop, J. G.2  Masereeuw, R.1  | |
[1] Radboud Univ Nijmegen, Med Ctr, Dept Pharmacol & Toxicol, Nijmegen Ctr Mol Life Sci, NL-6525 GA Nijmegen, Netherlands | |
[2] Radboud Univ Nijmegen, Med Ctr, Dept Physiol, Nijmegen Ctr Mol Life Sci, NL-6525 GA Nijmegen, Netherlands | |
[3] Radboud Univ Nijmegen, Med Ctr, Dept Biochem, Nijmegen Ctr Mol Life Sci, NL-6525 GA Nijmegen, Netherlands | |
[4] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, Nijmegen Ctr Mol Life Sci, NL-6525 GA Nijmegen, Netherlands | |
[5] Univ Hosp Ghent, Div Renal, Ghent, Belgium | |
[6] Catholic Univ Louvain, Dept Pediat, B-3000 Louvain, Belgium | |
关键词: Uremic toxins; Chronic kidney disease; Drug metabolism; UDP-glucuronosyltransferases; Mitochondria; | |
DOI : 10.1016/j.bbadis.2012.09.006 | |
来源: Elsevier | |
【 摘 要 】
During chronic kidney disease (CKD), drug metabolism is affected leading to changes in drug disposition. Furthermore, there is a progressive accumulation of uremic retention solutes due to impaired renal clearance. Here, we investigated whether uremic toxins can influence the metabolic functionality of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC) with the focus on UDP-glucuronosyltransferases (UGTs) and mitochondrial activity. Our results showed that ciPTEC express a wide variety of metabolic enzymes, including UGTs. These enzymes were functionally active as demonstrated by the glucuronidation of 7-hydroxycoumarin (7-OHC; K-m of 12 +/- 2 mu M and a V-max of 76 +/- 3 pmol/min/mg) and p-cresol (K-m of 33 +/- 13 mu M and a V-max of 266 +/- 25 pmol/min/mg). Furthermore, a wide variety of uremic toxins, including indole-3-acetic acid, indoxyl sulfate, phenylacetic acid and kynurenic acid, reduced 7-OHC glucuronidation with more than 30% as compared with controls (p<0.05), whereas UGT1A and UGT2B protein expressions remained unaltered. In addition, our results showed that several uremic toxins inhibited mitochondrial succinate dehydrogenase (i.e. complex II) activity with more than 20% as compared with controls (p<0.05). Moreover, indole-3-acetic acid decreased the reserve capacity of the electron transport system with 18% (p<0.03). In conclusion, this study shows that multiple uremic toxins inhibit UGT activity and mitochondrial activity in ciPTEC, thereby affecting the metabolic capacity of the kidney during CKD. This may have a significant impact on drug and uremic retention solute disposition in CKD patients. (c) 2012 Elsevier B.V. All rights reserved.
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