Cisplatin and Oxaliplatin, but Not Carboplatin and Nedaplatin, Are Substrates for Human Organic Cation Transporters (SLC22A1–3 and Multidrug and Toxin Extrusion Family)

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Abstract
We have examined the role of the human organic cation transporters [hOCTs and human novel organic cation transporter (hOCTN); SLC22A1–5] and apical multidrug and toxin extrusion (hMATE) in the cellular accumulation and cytotoxicity of platinum agents using the human embryonic kidney (HEK) 293 cells transiently transfected with the transporter cDNAs. Both the cytotoxicity and accumulation of cisplatin were enhanced by the expression of hOCT2 and weakly by hOCT1, and those of oxaliplatin were also enhanced by the expression of hOCT2 and weakly by hOCT3. The hOCT-mediated uptake of tetraethylammonium (TEA) was markedly decreased in the presence of cisplatin in a concentration-dependent manner. However, oxaliplatin showed almost no influence on the TEA uptakes in the HEK293 cells expressing hOCT1, hOCT2, and hOCT3. The hMATE1 and hMATE2-K, but not hOCTN1 and OCTN2, mediated the cellular accumulation of cisplatin and oxaliplatin without a marked release of lactate dehydrogenase. Oxaliplatin, but not cisplatin, markedly decreased the hMATE2-K-mediated TEA uptake. However, the inhibitory effect of cisplatin and oxaliplatin against the hMATE1-mediated TEA uptake was similar. The release of lactate dehydrogenase and the cellular accumulation of carboplatin and nedaplatin were not found in the HEK293 cells transiently expressing these seven organic cation transporters. These results indicate that cisplatin is a relatively good substrate of hOCT1, hOCT2, and hMATE1, and oxaliplatin is of hOCT2, hOCT3, hMATE1, and hMATE2-K. These transporters could play predominant roles in the tissue distribution and anticancer effects and/or adverse effects of platinum agent-based chemotherapy.