title: Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration.
abstract: 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±2μM and a V(max) of 76±3pmol/min/mg) and p-cresol (K(m) of 33±13μM and a V(max) of 266±25pmol/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.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: H A M
authors.initials: HA
authors.lastname: Mutsaers
authors.forename: M J G
authors.initials: MJ
authors.lastname: Wilmer
authors.forename: D
authors.initials: D
authors.lastname: Reijnders
authors.forename: J
authors.initials: J
authors.lastname: Jansen
authors.forename: P H H
authors.initials: PH
authors.lastname: van den Broek
authors.forename: M
authors.initials: M
authors.lastname: Forkink
authors.forename: E
authors.initials: E
authors.lastname: Schepers
authors.forename: G
authors.initials: G
authors.lastname: Glorieux
authors.forename: R
authors.initials: R
authors.lastname: Vanholder
authors.forename: L P
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: J G
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: R
authors.initials: R
authors.lastname: Masereeuw
mesh_terms: D002460:Cell Line; D003408:Cresols / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004579:Electron Transport; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D014468:Umbelliferones / Q000378:metabolism; D014511:Uremia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
chemical_list: D003408:Cresols; D004364:Pharmaceutical Preparations; D014468:Umbelliferones; C032538:4-cresol; C031477:7-hydroxycoumarin; D013385:Succinate Dehydrogenase; D014453:Glucuronosyltransferase