The organic cation transporter OCT2 mediates the uptake of <i>β</i>‐adrenoceptor antagonists across the apical membrane of renal LLC‐PK<sub>1</sub> cell monolayers

Dudley, Amanda; Bleasby, Kelly; Brown, Charles D.

doi:10.1038/sj.bjp.0703518

Cited by 66 publications

(44 citation statements)

References 23 publications

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“…Consistent with the fact that cimetidine is a substrate of renal organic cation transporters (Dudley et al, 2000;Ito et al, 2010), cimetidine acts as a competitive inhibitor of other substrates (Fig. 3).…”

Section: Discussionmentioning

confidence: 53%

Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney

Ito¹,

Kusuhara²,

Yokochi³

et al. 2011

J Pharmacol Exp Ther

185

129

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Cimetidine, an H 2 receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (K i ) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino)styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 M for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6 -7.8 M). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with K i values (M) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 M. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 M to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney-and liver-toplasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0-and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/min/kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.

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Section: Discussionmentioning

confidence: 53%

Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney

Ito¹,

Kusuhara²,

Yokochi³

et al. 2011

J Pharmacol Exp Ther

185

129

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“…The rOCT3 and mOCT3 clones were the generous gift from Dr. Vadivel Ganapathy (14,34) and hOCT2 from Dr. Kelly Bleasby (35).…”

Section: Methodsmentioning

confidence: 99%

Ventricular Choline Transport

Sweet

Miller

Pritchard

2001

Journal of Biological Chemistry

144

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To determine whether organic cation transporter (OCT) family members might mediate choline transport in choroid plexus (CP), the handling of choline by cloned transporters and by intact CP isolated from the adult rat was investigated. Expression of OCT1 and OCT2 in Xenopus oocytes increased hemicholinium-3-sensitive choline uptake. In contrast, OCT3 did not mediate choline transport. Estimated K m values for choline in rOCT1-, rOCT2-, and hOCT2-expressing oocytes were 346 ؎ 50, 441 ؎ 67, and 102 ؎ 80 M, respectively. Membrane potential was the major driving force for choline uptake in rat and human OCT2-expressing oocytes and in intact CP in vitro. Lowering of medium pH (6 versus 7.4) was equally effective at inhibiting choline uptake in CP, suggesting that there might be a non-OCT component of choline uptake that is responsive to an H ؉ gradient. However, choline efflux from CP was not stimulated by a trans-applied H ؉ gradient. Choline uptake by CP was Na ؉ -independent with an estimated K m of 183 M. Reverse transcriptase-polymerase chain reaction detected OCT2 and OCT3, but not OCT1, mRNA expression in CP. Transfection of intact CP with a rOCT2/green fluorescent protein fusion construct resulted in strong apical membrane fluorescence with no detectable signal in the basal and lateral plasma membranes. These data indicate that OCT2 mediates choline transport across the ventricular membrane of CP.

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“…3C, available at www.jneurosci.org as supplemental material). Because weakly basic lysosomotropic amines such as ammonium chloride are known to induce LMP by alkalinizing the intralysosomal acidic pH (Boya and Kroemer, 2008) and MPP ϩ is a quaternary ammonium compound able to alkalinize intracellular pH in some cellular settings (Dudley et al, 2000), we ruled out the possibility that MPP ϩ could directly induce LMP (supplemental Fig. 4D,E, available at www.jneurosci.org as supplemental material).…”

Section: Lmp Linked To Complex I Inhibition Is Mediated By Mitochondrmentioning

confidence: 99%

Pathogenic Lysosomal Depletion in Parkinson's Disease

Dehay¹,

Bové²,

et al. 2010

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Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including ␣-synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrialderived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4-phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PD.

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The organic cation transporter OCT2 mediates the uptake of β‐adrenoceptor antagonists across the apical membrane of renal LLC‐PK₁ cell monolayers

Cited by 66 publications

References 23 publications

Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney

Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney

Ventricular Choline Transport

Pathogenic Lysosomal Depletion in Parkinson's Disease

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The organic cation transporter OCT2 mediates the uptake of β‐adrenoceptor antagonists across the apical membrane of renal LLC‐PK1 cell monolayers

Cited by 66 publications

References 23 publications

Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney

Competitive Inhibition of the Luminal Efflux by Multidrug and Toxin Extrusions, but Not Basolateral Uptake by Organic Cation Transporter 2, Is the Likely Mechanism Underlying the Pharmacokinetic Drug-Drug Interactions Caused by Cimetidine in the Kidney

Ventricular Choline Transport

Pathogenic Lysosomal Depletion in Parkinson's Disease

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The organic cation transporter OCT2 mediates the uptake of β‐adrenoceptor antagonists across the apical membrane of renal LLC‐PK₁ cell monolayers