Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2
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Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. / Ciarimboli, Giuliano; Ludwig, Thomas; Lang, Detlef; Pavenstädt, Hermann; Koepsell, Hermann; Piechota, Hans-Jürgen; Haier, Jörg; Jaehde, Ulrich; Zisowsky, Jochen; Schlatter, Eberhard.
in: AM J PATHOL, Jahrgang 167, Nr. 6, 12.2005, S. 1477-84.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2
AU - Ciarimboli, Giuliano
AU - Ludwig, Thomas
AU - Lang, Detlef
AU - Pavenstädt, Hermann
AU - Koepsell, Hermann
AU - Piechota, Hans-Jürgen
AU - Haier, Jörg
AU - Jaehde, Ulrich
AU - Zisowsky, Jochen
AU - Schlatter, Eberhard
PY - 2005/12
Y1 - 2005/12
N2 - Cis-platin is an effective anti-neoplastic agent, but it is also highly nephrotoxic. Here, we clearly identify the human organic cation transporter 2 (hOCT2) as the critical transporter for cis-platin nephrotoxicity in isolated human proximal tubules and offer a potential mechanism for reducing nephrotoxicity in clinical practice. Interaction of cis-platin with hOCT2 in kidney or hOCT1 in liver was investigated with the fluorescent cation 4-[4-(dimethyl-amino)styril]-methylpyridinium in stably transfected HEK293 cells and for the first time in tissues physiologically expressing these transporters, human proximal tubules, and human hepatocyte couplets. Cis-platin (100 micromol/L) inhibited transport via hOCT2-HEK293 but not hOCT1-HEK293. In human proximal tubules cis-platin competed with basolateral organic cation transport, whereas it had no effect in tubules from a diabetic kidney or in hepatocytes. In hOCT2-HEK293 cells treated for 15 hours, incubation with cis-platin induced apoptosis, which was completely suppressed by contemporaneous incubation with the hOCT2 substrate cimetidine (100 micromol/L). These findings demonstrate that uptake of cis-platin is mediated by hOCT2 in renal proximal tubules, explaining its organ-specific toxicity. A combination of cis-platin with other substrates that compete for hOCT2 offers an effective option to decrease nephrotoxicity in the clinical setting.
AB - Cis-platin is an effective anti-neoplastic agent, but it is also highly nephrotoxic. Here, we clearly identify the human organic cation transporter 2 (hOCT2) as the critical transporter for cis-platin nephrotoxicity in isolated human proximal tubules and offer a potential mechanism for reducing nephrotoxicity in clinical practice. Interaction of cis-platin with hOCT2 in kidney or hOCT1 in liver was investigated with the fluorescent cation 4-[4-(dimethyl-amino)styril]-methylpyridinium in stably transfected HEK293 cells and for the first time in tissues physiologically expressing these transporters, human proximal tubules, and human hepatocyte couplets. Cis-platin (100 micromol/L) inhibited transport via hOCT2-HEK293 but not hOCT1-HEK293. In human proximal tubules cis-platin competed with basolateral organic cation transport, whereas it had no effect in tubules from a diabetic kidney or in hepatocytes. In hOCT2-HEK293 cells treated for 15 hours, incubation with cis-platin induced apoptosis, which was completely suppressed by contemporaneous incubation with the hOCT2 substrate cimetidine (100 micromol/L). These findings demonstrate that uptake of cis-platin is mediated by hOCT2 in renal proximal tubules, explaining its organ-specific toxicity. A combination of cis-platin with other substrates that compete for hOCT2 offers an effective option to decrease nephrotoxicity in the clinical setting.
KW - Annexin A5
KW - Apoptosis
KW - Cell Line
KW - Cisplatin
KW - Humans
KW - Kidney
KW - Kinetics
KW - Octamer Transcription Factor-1
KW - Octamer Transcription Factor-2
U2 - 10.1016/S0002-9440(10)61234-5
DO - 10.1016/S0002-9440(10)61234-5
M3 - SCORING: Journal article
C2 - 16314463
VL - 167
SP - 1477
EP - 1484
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 6
ER -