Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Münster, Germany.
Mol Pharm. 2011 Feb 7;8(1):270-9. doi: 10.1021/mp100329u. Epub 2010 Dec 2.
Anticancer treatment with ifosfamide but not with its structural isomer cyclophosphamide is associated with development of renal Fanconi syndrome leading to diminished growth in children and bone problems in adults. Since both cytotoxics share the same principal metabolites, we investigated whether a specific renal uptake of ifosfamide is the basis for this differential effect. First we studied the interaction of these cytotoxics using cells transfected with organic anion or cation transporters and freshly isolated murine and human proximal tubules with appropriate tracers. Next we determined changes in membrane voltage in proximal tubular cells to understand their differentiated nephrotoxicity. Ifosfamide but not cyclophosphamide was significantly transported into cells expressing human organic cation transporter 2 (hOCT2) while both did not interact with organic anion transporters. This points toward a specific interaction of ifosfamide with hOCT2, which is the main OCT isoform in human kidney. In isolated human proximal tubules ifosfamide also interacted with organic cation transport. This interaction was also seen in isolated mouse proximal tubules; however, it was absent in tubules from OCT-deficient mice, illustrating the biological importance of this selective transport. Ifosfamide decreased the viability of cells expressing hOCT2, but not that of control cells. Coadministration of cimetidine, a known competitive substrate of hOCT2, completely prevented this ifosfamide-induced toxicity. Finally, ifosfamide but not cyclophosphamide depolarized proximal tubular cells. We propose that the nephrotoxicity of ifosfamide is due to its selective uptake by hOCT2 into renal proximal tubular cells, and that coadministration of cimetidine may be used to prevent ifosfamide-induced nephrotoxicity.
异环磷酰胺而非其结构类似物环磷酰胺的抗癌治疗与肾范可尼综合征的发展有关，导致儿童生长受限和成人骨骼问题。由于这两种细胞毒性药物具有相同的主要代谢物，我们研究了异环磷酰胺是否存在特定的肾摄取，这是造成这种差异效应的基础。首先，我们使用转染有机阴离子或阳离子转运体的细胞以及适当示踪剂的新鲜分离的鼠和人近端肾小管研究了这些细胞毒性药物的相互作用。接下来，我们测定了近端肾小管细胞的膜电压变化，以了解其分化的肾毒性。只有异环磷酰胺而不是环磷酰胺显著转运到表达人有机阳离子转运体 2 (hOCT2)的细胞中，而两者均不与有机阴离子转运体相互作用。这表明异环磷酰胺与 hOCT2 有特异性相互作用，而 hOCT2 是人类肾脏中主要的 OCT 同工酶。在分离的人近端肾小管中，异环磷酰胺也与有机阳离子转运相互作用。这种相互作用在分离的鼠近端肾小管中也存在，但在 OCT 缺乏的小鼠肾小管中不存在，说明了这种选择性转运的生物学重要性。异环磷酰胺降低了表达 hOCT2 的细胞的活力，但对对照细胞没有影响。西咪替丁是 hOCT2 的已知竞争性底物，与异环磷酰胺同时给药可完全预防这种异环磷酰胺诱导的毒性。最后，只有异环磷酰胺而非环磷酰胺使近端肾小管细胞去极化。我们提出，异环磷酰胺的肾毒性是由于其被 hOCT2 选择性摄取到肾近端肾小管细胞中，而同时给予西咪替丁可能用于预防异环磷酰胺引起的肾毒性。
