Functional characterization of ORCTL2 ‐ an organic cation transporter expressed in the renal proximal tubules

Reece, Mark; Prawitt, Dirk; Landers, John E.; Kast, Christina; Gros, Piet; Housman, David E.; Zabel, Bernhard

doi:10.1016/s0014-5793(98)00907-7

Cited by 24 publications

(15 citation statements)

References 21 publications

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“…However, although CQ may be a substrate of multiple drug resistance 1 protein (Polli et al, 2001) and organic cation transporter-like 2 protein (Reece et al, 1998), both of these are involved in the excretion of drugs from cytosol to the extracellular medium. No active transporter mechanisms have been found to play a role in CQ cellular uptake.…”

Section: Discussionmentioning

confidence: 99%

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

Zheng

Zhang

Rosania³

2010

J Pharmacol Exp Ther

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In vivo, the weakly basic, lipophilic drug chloroquine (CQ) accumulates in the kidney to concentrations more than a thousand-fold greater than those in plasma. To study the cellular pharmacokinetics of chloroquine in cells derived from the distal tubule, Madin-Darby canine kidney cells were incubated with CQ under various conditions. CQ progressively accumulated without exhibiting steady-state behavior. Experiments failed to yield evidence that known active transport mechanisms mediated CQ uptake at the plasma membrane. CQ induced a phospholipidosis-like phenotype, characterized by the appearance of numerous multivesicular and multilamellar bodies (MLBs/ MVBs) within the lumen of expanded cytoplasmic vesicles. Other induced phenotypic changes including changes in the volume and pH of acidic organelles were measured, and the integrated effects of all these changes were computationally modeled to establish their impact on intracellular CQ mass accumulation. Based on the passive transport behavior of CQ, the measured phenotypic changes fully accounted for the continuous, nonsteady-state CQ accumulation kinetics. Consistent with the simulation results, Raman confocal microscopy of live cells confirmed that CQ became highly concentrated within induced, expanded cytoplasmic vesicles that contained multiple MLBs/MVBs. Progressive CQ accumulation was increased by sucrose, a compound that stimulated the phospholipidosislike phenotype, and was decreased by bafilomycin A1, a compound that inhibited this phenotype. Thus, phospholipidosisassociated changes in organelle structure and intracellular membrane content can exert a major influence on the local bioaccumulation and biodistribution of drugs.

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Section: Discussionmentioning

confidence: 99%

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

Zheng

Zhang

Rosania³

2010

J Pharmacol Exp Ther

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“…The functional study characterizing IMPT1/ORCTL2 revealed that the encoded protein could confer resistance to chloroquine and guanidine in bacteria (10). The allelic expression bias observed in peripheral blood leukocyte potentially might be diagnostic indicator of the efficacy of drugs for individuals.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Heterogeneity at Imprinted Loci in Normal Populations

Sakatani

Wei

Katoh

et al. 2001

Biochemical and Biophysical Research Communications

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“…The sense SLC22A18 gene codes for a polyspecific organic cation transporter that is expressed in liver and kidney (Cooper et al, 1998). It can confer resistance to chloroquine and quinidine when overexpressed in bacteria (Reece et al,1998), which suggests a role in the transport of chloroquine and quinidine related compounds in kidneys. Somatic mutations have been found in this gene in tumor samples (Schwienbacher et al, 1998).…”

Section: Introductionmentioning

confidence: 99%