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

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.Four platinum-based anticancer drugs are currently registered for clinical use. cis-Diamminedichloroplatinum II (cisplatin) has been clinically used for over 30 years and continues to play an essential role in cancer chemotherapy against solid tumors of the prostate, bladder, colon, lung, testis, liver, and brain (Ho et al., 2003). However, severe nephrotoxicity limits its clinical application because it was reported that an increase in the serum creatinine concentration was observed in 41% of patients treated with a high dose of cisplatin (de Jongh et al., 2003). cis-Diammine(1,1-cyclobutanedicarboxylato)platinum II (carboplatin), trans-L-1,2-diaminocyclohexaneoxalatoplatinum II (oxaliplatin), and cis-diammineglycolatoplatinum (nedaplatin) are analogs of cisplatin and show a lowered nephrotoxicity compared with cisplatin. However, it is not clear why the nephrotoxicity of these analogs is low, although cisplatin induces severe nephrotoxicity. The chemical structures of platinum agents are shown in Fig.

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

“…For instance, oxaliplatin and cimetidine are substrates for both OCT1 and OCT3. [22][23][24][25] Our transport studies identify metformin as an OCT3 substrate (Fig. 4) with an affinity for OCT3 similar to that for OCT1 21,28,29 and a twofold higher maximal transport rate compared with OCT1.…”

“…OCT1 substrates include antiviral drugs [18][19][20] and the antidiabetic drug metformin. 21 The anticancer drug oxaliplatin, 22,23 the histamine H 2 receptor antagonist cimetidine, 24,25 and the antiviral drug lamivudine 19,20 are substrates for both OCT1 and OCT3. Notably, hepatocytes are the pharmacological target cells of lamivudine, when it is used to treat chronic hepatitis B, 26 and of metformin.…”

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

“…Unlike other platinum compounds, carboplatin is excreted mainly via glomerular filtration (Sorensen et al, 1992) and is not transported by organic cation transporters including hOCT1 and hOCT2 (Yonezawa et al, 2006). Moreover, a previous study reported that the accumulation of p-aminohippurate (a typical substrate of hOATs) was not inhibited by carboplatin in the experiment using rat renal cortical slices (Kanou et al, 2004).…”

Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

“…27,28 As there is little transport of cisplatin by MATE1 and MATE2-K, cisplatin is accumulated in the proximal tubular cells causing nephrotoxicity. A low-nephrotoxic platinum anticancer agent, oxaliplatin, was transported by OCT2 and MATE2-K, 27,28 suggesting that oxaliplatin does not accumulate in the renal proximal tubular cells. Therefore, loss of function of MATE2-K caused by cSNPs may lead to the accumulation of oxaliplatin in the kidney and the subsequent nephrotoxicity.…”