eCite Digital Repository

Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons

Citation

Jong, NN and Nakanishi, T and Liu, JJ and Tamai, I and McKeage, MJ, Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons, Journal of Pharmacology and Experimental Therapeutics, 338 pp. 537-547. ISSN 0022-3565 (2011) [Refereed Article]


Preview
PDF
Restricted - Request a copy
2Mb
  

Copyright Statement

Copyright 2011 The American Society for Pharmacology and Experimental Therapeutics

Official URL: http://jpet.aspetjournals.org/site/misc/terms.xhtm...

DOI: doi:10.1124/jpet.111.181297

Abstract

ABSTRACT 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 those of OCTs. [14C]Oxaliplatin uptake, platinum accumulation, and cytotoxicity were determined in OCTN-overexpressing human embryonic kidney (HEK) 293 cells and primary cultures of rat DRG neurons. Levels of mRNA and functional activities of rat (r)Octns and rOcts in rat DRG tissue and primary cultures were characterized using reverse transcription-polymerase chain reaction and uptake of model OCT/OCTN substrates, including [3H]1- methyl-4-phenylpyridinium (MPP) (OCT13), [14C]tetraethylammonium bromide (TEA) (OCT13 and OCTN1/2), [3H]ergothioneine (OCTN1), and [3H]L-carnitine (OCTN2). HEK293 cells overexpressing rOctn1, rOctn2, human OCTN1, and human OCTN2 showed increased uptake and cytotoxicity of oxaliplatin compared with mock-transfected HEK293 controls; in addition, both uptake and cytotoxicity were inhibited by ergothioneine and L-carnitine. The uptake of ergothioneine mediated by OCTN1 and of L-carnitine mediated by OCTN2 was decreased during oxaliplatin exposure. rOctn1 and rOctn2 mRNA was readily detected in rat DRG tissue, and they were functionally active in cultured rat DRG neurons, more so than rOct1, rOct2, or rOct3.DRGneuronal accumulation of [14C]oxaliplatin and platinum during oxaliplatin exposure depended on time, concentration, temperature, and sodium and was inhibited by ergothioneine and 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 treatmentlimiting neurotoxicity more so than OCTN2 or OCTs.

Item Details

Item Type:Refereed Article
Keywords:Oxaliplatin, organic cation transporter, dorsal root ganglion
Research Division:Medical and Health Sciences
Research Group:Pharmacology and Pharmaceutical Sciences
Research Field:Clinical Pharmacology and Therapeutics
Objective Division:Health
Objective Group:Other Health
Objective Field:Health not elsewhere classified
Author:Liu, JJ (Dr Johnson Liu)
ID Code:86354
Year Published:2011
Web of Science® Times Cited:57
Deposited By:Pharmacy
Deposited On:2013-09-06
Last Modified:2014-04-17
Downloads:0

Repository Staff Only: item control page