Differential Interaction of Dantrolene, Glafenine, Nalidixic Acid, and Prazosin with Human Organic Anion Transporters 1 and 3
| Autor: | Yohannes Hagos, Maja Henjakovic, Gerhard Burckhardt, Birgitta C. Burckhardt |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Nalidixic acid Organic anion transporter 1 Estrone Metabolic Clearance Rate Cell Culture Techniques Organic Anion Transport Protein 1 Organic Anion Transporters Sodium-Independent Pharmacology Transfection Binding Competitive Dantrolene Substrate Specificity Nalidixic Acid Radioligand Assay 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Prazosin Humans Binding site biology Chemistry Apical membrane Renal Elimination HEK293 Cells 030104 developmental biology Biochemistry biology.protein Molecular Medicine Glafenine 030217 neurology & neurosurgery Protein Binding medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 362:450-458 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | In renal proximal tubule cells, the organic anion transporters 1 and 3 (OAT1 and OAT3) in the basolateral membrane and the multidrug resistance-associated protein 4 (MRP4) in the apical membrane share substrates and co-operate in renal drug secretion. We hypothesized that recently identified MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin also interact with human OAT1 and/or OAT3 stably transfected in human embryonic kidney 293 cells. These four drugs were tested as possible inhibitors of p-[3H]aminohippurate (PAH) and [14C]glutarate uptake by OAT1, and of [3H]estrone-3-sulfate (ES) uptake by OAT3. In addition, we explored whether these drugs decrease the equilibrium distribution of radiolabeled PAH, glutarate, or ES, an approach intended to indirectly suggest drug/substrate exchange through OAT1 and OAT3. With OAT3, a dose-dependent inhibition of [3H]ES uptake and a downward shift in [3H]ES equilibrium were observed, indicating that all four drugs bind to OAT3 and may possibly be translocated. In contrast, the interaction with OAT1 was more complex. With [14C]glutarate as substrate, all four drugs inhibited uptake but only glafenine and nalidixic acid shifted glutarate equilibrium. Using [3H]PAH as a substrate of OAT1, nalidixic acid inhibited but dantrolene, glafenine, and prazosin stimulated uptake. Nalidixic acid decreased equilibrium content of [3H]PAH, suggesting that it may possibly be exchanged by OAT1. Taken together, OAT1 and OAT3 interact with the MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin, indicating overlapping specificities. At OAT1, more than one binding site must be assumed to explain substrate and drug-dependent stimulation and inhibition of transport activity. |
| Databáze: | OpenAIRE |
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