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Decreased expression of organic cation transporters, Oct1 and Oct2, in brain microvessels and its implication to MPTP-induced dopaminergic toxicity in aged mice.

ABSTRACT: This study was to investigate the influence of age on the expression of organic cation transporters (OCTs) that belong to the SLC22 family in brain microvessels (BMVs) and its implications for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity in mice. Here, we showed that Oct1 and Oct2, but not Oct3, mRNAs were detected and enriched (compared with cerebral cortex) in BMVs of C57BL/6 (B6) mice using reverse transcription-quantitative PCR (RT-qPCR), and immunofluorescence analysis further revealed that Oct1 and Oct2 proteins were colocalized with endothelial markers. Both the mRNA and protein levels of Oct1 and Oct2 were reduced in aged mice. After an intraperitoneal administration of MPTP, brain extracellular levels of MPTP and 1-methyl-4-phenyl-pyridinium (MPP(+)) were much lower in aged mice and in Oct1/2(-/-) mice compared with younger mice and wild-type control mice, respectively. Knockout of Oct1/Oct2 protected Oct1/2(-/-) mice from MPTP-induced neurotoxicity, whereas the loss of tyrosine hydroxylase (TH)-positive neurons was slightly greater in aged than in younger mice. However, intrastriatal infusion of low-dose MPTP caused more severe dopaminergic toxicity in the substantia nigra of both aged mice and Oct1/2(-/-) mice. These findings show that age-dependent downregulation or knockout of Oct1/Oct2 in BMVs may reduce the transport of MPTP, which, in part, affects its dopaminergic toxicity.

SUBMITTER: Wu KC

PROVIDER: S-EPMC4294392 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Decreased expression of organic cation transporters, Oct1 and Oct2, in brain microvessels and its implication to MPTP-induced dopaminergic toxicity in aged mice.

Wu Kuo-Chen KC Lu Ya-Hsuan YH Peng Yi-Hsuan YH Tsai Ting-Fen TF Kao Yu-Han YH Yang Hui-Ting HT Lin Chun-Jung CJ

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20140924 1

This study was to investigate the influence of age on the expression of organic cation transporters (OCTs) that belong to the SLC22 family in brain microvessels (BMVs) and its implications for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity in mice. Here, we showed that Oct1 and Oct2, but not Oct3, mRNAs were detected and enriched (compared with cerebral cortex) in BMVs of C57BL/6 (B6) mice using reverse transcription-quantitative PCR (RT-qPCR), and immunofluore ...[more]

PMID: 25248837

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Project description:Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity.In this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs.We characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 ?M and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism.We confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine's potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine pharmacokinetics in humans remain to be analyzed.

Dataset Information

Decreased expression of organic cation transporters, Oct1 and Oct2, in brain microvessels and its implication to MPTP-induced dopaminergic toxicity in aged mice.

Publications

Decreased expression of organic cation transporters, Oct1 and Oct2, in brain microvessels and its implication to MPTP-induced dopaminergic toxicity in aged mice.

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