L-tetrahydropalmatine reduces oxaliplatin accumulation in the dorsal root ganglion and mitochondria through selectively inhibiting the transporter-mediated uptake thereby attenuates peripheral neurotoxicity. (July 2021)

• Record Type: Journal Article
• Authors: Yi, Yaodong; Li, Liping; Song, Feifeng; Li, Ping; Chen, Mingyang; Ni, Shixin; Zhang, Hengbin; Zhou, Hui; Zeng, Su; Jiang, Huidi
• Is Part Of: Toxicology. Volume 459(2021)
• Publication Date: 2021-07
• Subjects: DRG dorsal root ganglion -- DMEM Dulbecco's modified Eagle medium -- FBS Foetal bovine serum -- HBSS Hank's balanced salt solution -- iv intravenous administration -- ICP-MS inductively coupled plasma mass spectrometry -- ig intragastrical administration -- LDH lactate dehydrogenase -- L-THP L-tetrahydropalmatine -- MATE multidrug and toxin extrusion -- MDCK Madin–Darby canine kidney -- MRP multidrug resistance-associated protein -- OCT organic cation transporter -- OCTN organic cation/carnitine transporter -- OXA oxaliplatin -- PBS phosphate buffer saline -- PMSF phenylmethylsulfonyl fluoride -- Pt platinum；RPMI, Roswell Park Memorial Institute 1640 medium -- SDS sodium dodecyl sulfate -- SEM standard error of mean -- SLC solute carrier -- VDAC1 Voltage Dependent Anion Channel Protein 1; L-tetrahydropalmatine -- Oxaliplatin -- Peripheral neurotoxicity -- OCT2 -- OCTN1; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152853
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: OCT2 and OCTN1/2, especially OCTN1 mediates mitochondrial uptake of OXA. L-THP reduces OXA uptake in DRG and mitochondria via inhibiting OCT2 and OCTN1. L-THP attenuates OXA-induced peripheral neurotoxicity but does not reduce its efficiency. Abstract: Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo . Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1−100 μM) reduced OXA (40 μM) induced cytotoxicity in MDCK-hOCT2 (Madin–Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5–20 mg/kg for mice, 10–40 mg/kg for rats; twice a week, iv or ig ) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv ) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1−100 μM for cells; 10–20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 μM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.