The organic cation/carnitine transporters OCTN1 and OCTN2 are related to other organic cation transporters (OCT1, OCT2 and OCT3) known for transporting oxaliplatin, an anticancer drug with dose-limiting neurotoxicity. In this study we sought to determine whether OCTN1 and OCTN2 also transported oxaliplatin, and to characterize their functional expression and contributions to its neuronal accumulation and neurotoxicity in dorsal root ganglion (DRG) neurons, relative to that of OCTs. [14C] Oxaliplatin uptake, platinum accumulation and cytotoxicity were determined in OCTN-over-expressing HEK293 cells and primary cultures of rat DRG neurons. Levels of mRNA, protein and functional activities of rOctns and rOcts in rat DRG tissue and primary cultures were characterized using RT-PCR, Western blotting and uptake of model OCT/OCTN substrates, including [3H] MPP+ (OCT1-3), [14C] TEA+ (OCT1-3; OCTN1/2), [3H] ergothioneine (OCTN1) and [3H] L-carnitine (OCTN2). HEK293 cells over-expressing rOctn1, rOctn2, hOCTN1 and hOCTN2 showed increased uptake and cytotoxicity of oxaliplatin compared to mock-transfected HEK293 controls and it was inhibited by ergothioneine and L-carnitine. The uptake of ergothioneine mediated by OCTN1, and L-carnitine mediated by OCTN2, was decreased during oxaliplatin exposure. OCTN1 and OCTN2 mRNA was readily detected in rat DRG tissue and they were functionally active in cultured rat DRG neurons, more so than OCT1, OCT2 or OCT3. DRG neuronal accumulation of [14C] Oxaliplatin and platinum during oxaliplatin exposure depended upon time, concentration, temperature and sodium, and was inhibited by ergothioneine, to a lesser extent by L-carnitine but not by MPP+. Loss of DRG neuronal viability during oxaliplatin exposure was inhibited by ergothioneine but not by L-carnitine or MPP+. OCTN1 and OCTN2 both transport oxaliplatin and are functionally expressed by DRG neurons. OCTN1-mediated transport of oxaliplatin appears to contribute to its neuronal accumulation and treatment-limiting neurotoxicity more so than OCTN2 or OCTs.
- chemotherapy-induced neurotoxicity
- dorsal root ganglion
- drug uptake
- organic cation transporters (OCTs)
- organic cation/carnitine transporters (OCTNs)
- Received March 7, 2011.
- Revision received May 10, 2011.
- Accepted May 20, 2011.
- The American Society for Pharmacology and Experimental Therapeutics