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Drug Metab Dispos. 2018 May;46(5):592-599. doi: 10.1124/dmd.117.079384. Epub 2018 Mar 7.

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity.

Author information

1
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands (T.T.G.N., J.G.P.P., D.D., D.K., K.J., A.H.V.A., F.G.M.R., M.J.W.); Department of Physical Chemistry/Bioenergetics, Institute of Chemistry PC14, Technical University of Berlin, Berlin, Germany (N.N.T., T.F.); and Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands (K.J., R.M.).
2
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands (T.T.G.N., J.G.P.P., D.D., D.K., K.J., A.H.V.A., F.G.M.R., M.J.W.); Department of Physical Chemistry/Bioenergetics, Institute of Chemistry PC14, Technical University of Berlin, Berlin, Germany (N.N.T., T.F.); and Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands (K.J., R.M.) martijn.wilmer@radboudumc.nl.

Abstract

Cisplatin is a cytostatic drug used for treatment of solid organ tumors. The main adverse effect is organic cation transporter 2 (OCT2)-mediated nephrotoxicity, observed in 30% of patients. The contribution of other renal drug transporters is elusive. Here, cisplatin-induced toxicity was evaluated in human-derived conditionally immortalized proximal tubule epithelial cells (ciPTEC) expressing renal drug transporters, including OCT2 and organic anion transporters 1 (OAT1) or 3 (OAT3). Parent ciPTEC demonstrated OCT2-dependent cisplatin toxicity (TC50 34 ± 1 μM after 24-hour exposure), as determined by cell viability. Overexpression of OAT1 and OAT3 resulted in reduced sensitivity to cisplatin (TC50 45 ± 6 and 64 ± 11 μM after 24-hour exposure, respectively). This effect was independent of OAT-mediated transport, as the OAT substrates probenecid and diclofenac did not influence cytotoxicity. Decreased cisplatin sensitivity in OAT-expressing cells was associated directly with a trend toward reduced intracellular cisplatin accumulation, explained by reduced OCT2 gene expression and activity. This was evaluated by Vmax of the OCT2-model substrate ASP+ (23.5 ± 0.1, 13.1 ± 0.3, and 21.6 ± 0.6 minutes-1 in ciPTEC-parent, ciPTEC-OAT1, and ciPTEC-OAT3, respectively). Although gene expression of cisplatin efflux transporter multidrug and toxin extrusion 1 (MATE1) was 16.2 ± 0.3-fold upregulated in ciPTEC-OAT1 and 6.1 ± 0.7-fold in ciPTEC-OAT3, toxicity was unaffected by the MATE substrate pyrimethamine, suggesting that MATE1 does not play a role in the current experimental set-up. In conclusion, OAT expression results in reduced cisplatin sensitivity in renal proximal tubule cells, explained by reduced OCT2-mediated uptake capacity. In vitro drug-induced toxicity studies should consider models that express both OCT and OAT drug transporters.

PMID:
29514829
DOI:
10.1124/dmd.117.079384

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