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.
authors.affiliation: Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster, Germany. gciari@uni-muenster.de
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Detlef
authors.initials: D
authors.lastname: Lang
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Piechota
authors.forename: Jörg
authors.initials: J
authors.lastname: Haier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaehde
authors.forename: Jochen
authors.initials: J
authors.lastname: Zisowsky
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007700:Kinetics; D050811:Octamer Transcription Factor-1 / Q000187:drug effects / Q000378:metabolism*; D050813:Octamer Transcription Factor-2 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; C494165:POU2F1 protein, human; D002945:Cisplatin