Tags

Type your tag names separated by a space and hit enter

Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons.
J Pharmacol Exp Ther. 2011 Aug; 338(2):537-47.JP

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. [(14)C]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 [(3)H]1-methyl-4-phenylpyridinium (MPP(+)) (OCT1-3), [(14)C]tetraethylammonium bromide (TEA(+)) (OCT1-3 and OCTN1/2), [(3)H]ergothioneine (OCTN1), and [(3)H]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. DRG neuronal accumulation of [(14)C]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 treatment-limiting neurotoxicity more so than OCTN2 or OCTs.

Authors+Show Affiliations

Cancer Clinical Pharmacology Research Group, Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, University of Auckland, 85 Park Rd., Grafton, Private Bag 92019, Auckland 1023, New Zealand.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21606177

Citation

Jong, Nancy N., et al. "Oxaliplatin Transport Mediated By Organic Cation/carnitine Transporters OCTN1 and OCTN2 in Overexpressing Human Embryonic Kidney 293 Cells and Rat Dorsal Root Ganglion Neurons." The Journal of Pharmacology and Experimental Therapeutics, vol. 338, no. 2, 2011, pp. 537-47.
Jong NN, Nakanishi T, Liu JJ, et al. Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 2011;338(2):537-47.
Jong, N. N., Nakanishi, T., Liu, J. J., Tamai, I., & McKeage, M. J. (2011). Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. The Journal of Pharmacology and Experimental Therapeutics, 338(2), 537-47. https://doi.org/10.1124/jpet.111.181297
Jong NN, et al. Oxaliplatin Transport Mediated By Organic Cation/carnitine Transporters OCTN1 and OCTN2 in Overexpressing Human Embryonic Kidney 293 Cells and Rat Dorsal Root Ganglion Neurons. J Pharmacol Exp Ther. 2011;338(2):537-47. PubMed PMID: 21606177.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons. AU - Jong,Nancy N, AU - Nakanishi,Takeo, AU - Liu,Johnson J, AU - Tamai,Ikumi, AU - McKeage,Mark J, Y1 - 2011/05/23/ PY - 2011/5/25/entrez PY - 2011/5/25/pubmed PY - 2011/9/29/medline SP - 537 EP - 47 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 338 IS - 2 N2 - 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. [(14)C]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 [(3)H]1-methyl-4-phenylpyridinium (MPP(+)) (OCT1-3), [(14)C]tetraethylammonium bromide (TEA(+)) (OCT1-3 and OCTN1/2), [(3)H]ergothioneine (OCTN1), and [(3)H]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. DRG neuronal accumulation of [(14)C]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 treatment-limiting neurotoxicity more so than OCTN2 or OCTs. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/21606177/Oxaliplatin_transport_mediated_by_organic_cation/carnitine_transporters_OCTN1_and_OCTN2_in_overexpressing_human_embryonic_kidney_293_cells_and_rat_dorsal_root_ganglion_neurons_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21606177 DB - PRIME DP - Unbound Medicine ER -