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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, Vol. 167, No. 6, 12.2005, p. 1477-84.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Ciarimboli, G, Ludwig, T, Lang, D, Pavenstädt, H, Koepsell, H, Piechota, H-J, Haier, J, Jaehde, U, Zisowsky, J & Schlatter, E 2005, 'Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2', AM J PATHOL, vol. 167, no. 6, pp. 1477-84. https://doi.org/10.1016/S0002-9440(10)61234-5

APA

Ciarimboli, G., Ludwig, T., Lang, D., Pavenstädt, H., Koepsell, H., Piechota, H-J., Haier, J., Jaehde, U., Zisowsky, J., & Schlatter, E. (2005). Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. AM J PATHOL, 167(6), 1477-84. https://doi.org/10.1016/S0002-9440(10)61234-5

Vancouver

Ciarimboli G, Ludwig T, Lang D, Pavenstädt H, Koepsell H, Piechota H-J et al. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. AM J PATHOL. 2005 Dec;167(6):1477-84. https://doi.org/10.1016/S0002-9440(10)61234-5

Bibtex

@article{d5e61ec6d3e84fa79c1305ffd91e4a41,
title = "Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2",
abstract = "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.",
keywords = "Annexin A5, Apoptosis, Cell Line, Cisplatin, Humans, Kidney, Kinetics, Octamer Transcription Factor-1, Octamer Transcription Factor-2",
author = "Giuliano Ciarimboli and Thomas Ludwig and Detlef Lang and Hermann Pavenst{\"a}dt and Hermann Koepsell and Hans-J{\"u}rgen Piechota and J{\"o}rg Haier and Ulrich Jaehde and Jochen Zisowsky and Eberhard Schlatter",
year = "2005",
month = dec,
doi = "10.1016/S0002-9440(10)61234-5",
language = "English",
volume = "167",
pages = "1477--84",
journal = "AM J PATHOL",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "6",

}

RIS

TY - JOUR

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 -