Common Drugs Inhibit Human Organic Cation Transporter 1 (OCT1)-Mediated Neurotransmitter Uptake

Boxberger, Kelli H.; Hagenbuch, Bruno; Lampe, Jed N.

doi:10.1124/dmd.113.055095

Cited by 57 publications

(56 citation statements)

References 43 publications

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“…HEK-OCT1 cells exhibited enhanced verapamil-inhibitable accumulation of dopamine comparatively to HEK-MOCK cells (Fig 5A), thus fully confirming that OCT1 handles dopamine [52]. Allethrin used at 10, 100 or 300 μM was found to significantly inhibit this OCT1-mediated transport of dopamine (Fig 5B); tetramethrin also decreased it, but only when used at 100 or 300 μM (Fig 5B).…”

Section: Resultssupporting

confidence: 60%

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

et al. 2017

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Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 μM (OCT1 inhibition by allethrin) to 77.6 μM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 μM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.

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Section: Resultssupporting

confidence: 60%

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

et al. 2017

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“…Localized to the sinusoidal membrane of hepatocytes, OCT1 mediates the hepatic uptake of a diverse array of small positively charged hydrophilic compounds, including many endogenous bioactive amines 1 (e.g., dopamine, histamine, and serotonin). We recently identified OCT1 as a high-capacity transporter of thiamine in the liver and showed that the transporter plays a key role in modulating hepatic energy status and lipid content.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

et al. 2017

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Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP+ in cells overexpressing human OCT1. Thirty competitive OCT1 ligands, defined as ligands predicted in silico as well as found by HTS, were identified. Of the 167 ligands identified by HTS, five were predicted to potentially cause clinical drug interactions. Finally, virtual screening of 29 332 metabolites predicted 146 competitive OCT1 ligands, of which an endogenous neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, was experimentally validated. In conclusion, by combining docking and in vitro HTS, competitive and noncompetitive ligands of OCT1 can be predicted.

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“…To examine this possibility, we tested successfully some OCT1 inhibitors and found verapamil the most suitable one. We used verapamil in a concentration of 32x the IC 50 for the OCT1 substrate metformin [15], 14 times the IC 50 for serotonin [16], and 6x the IC 50 for tetraethylammonium TEA [17], to achieve a nearly complete inhibition of OCT1-mediated transport. After 5 min incubation of the cell suspensions with verapamil, we repeated the addition of the FC5-208A during the course of the same mass spectrometric experiment as performed in Fig.…”

Section: Resultsmentioning

confidence: 99%

CO2 Permeability of Rat Hepatocytes and Relation of CO2 Permeability to CO2 Production

Arias-Hidalgo

Yuan

Carta

et al. 2018

Cell Physiol Biochem

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Background/Aims: It has been described that cells in culture with very low oxidative metabolism possess a low CO₂ membrane permeability, P_CO2, of ∼ 0.01 cm/s. On the other hand, cardiomyocytes and mitochondria with extremely high rates of O₂ consumption exhibit very high CO₂ membrane permeabilities of 0.1 and 0.3 cm/s, repectively. To ascertain that this represents a systematic relationship, we determine here P_CO2 of hepatocytes, which exhibit an intermediate rate of O₂ consumption. Methods: We isolated intact hepatocytes with vitalities of ∼ 70% from rat liver and measured their CO₂ permeability by the previously published mass spectrometric ¹⁸O exchange technique. Results: We find a P_CO2 of hepatocytes of 0.03 cm/s in the presence of FC5-208A and verapamil. FC5-208A was necessary to inhibt extracellular carbonic anhydrase, and verapamil was necessary to inhibit intracellular uptake of FC5-208A by the organic cation transporter OCT1 of hepatocytes. Conclusion: Rat hepatocytes with their intermediate rate of oxygen consumption also possess an intermediate CO₂ permeability. From pairs of data for five types of cells/organelles, we find an excellent positive linear correlation between P_CO2 and metabolic rate, suggesting an adaptation of P_CO2 to the rate of O₂ consumption.

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Common Drugs Inhibit Human Organic Cation Transporter 1 (OCT1)-Mediated Neurotransmitter Uptake

Cited by 57 publications

References 43 publications

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

CO2 Permeability of Rat Hepatocytes and Relation of CO2 Permeability to CO2 Production

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