Modulation of Multidrug Resistance Protein 1-mediated Transport Processes by the Antiviral Drug Ritonavir in Cultured Primary Astrocytes
© 2023. The Author(s)..
The Multidrug Resistance Protein 1 (Mrp1) is an ATP-dependent efflux transporter and a major facilitator of drug resistance in mammalian cells during cancer and HIV therapy. In brain, Mrp1-mediated GSH export from astrocytes is the first step in the supply of GSH precursors to neurons. To reveal potential mechanisms underlying the drug-induced modulation of Mrp1-mediated transport processes, we investigated the effects of the antiviral drug ritonavir on cultured rat primary astrocytes. Ritonavir strongly stimulated the Mrp1-mediated export of glutathione (GSH) by decreasing the Km value from 200 nmol/mg to 28 nmol/mg. In contrast, ritonavir decreased the export of the other Mrp1 substrates glutathione disulfide (GSSG) and bimane-glutathione. To give explanation for these apparently contradictory observations, we performed in silico docking analysis and molecular dynamics simulations using a homology model of rat Mrp1 to predict the binding modes of ritonavir, GSH and GSSG to Mrp1. The results suggest that ritonavir binds to the hydrophilic part of the bipartite binding site of Mrp1 and thereby differently affects the binding and transport of the Mrp1 substrates. These new insights into the modulation of Mrp1-mediated export processes by ritonavir provide a new model to better understand GSH-dependent detoxification processes in brain cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
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| Enthalten in: |
Neurochemical research - 49(2024), 1 vom: 29. Jan., Seite 66-84 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Arend, Christian [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.01.2024 Date Revised 12.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s11064-023-04008-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © 2023. The Author(s). | ||
| 520 | |a The Multidrug Resistance Protein 1 (Mrp1) is an ATP-dependent efflux transporter and a major facilitator of drug resistance in mammalian cells during cancer and HIV therapy. In brain, Mrp1-mediated GSH export from astrocytes is the first step in the supply of GSH precursors to neurons. To reveal potential mechanisms underlying the drug-induced modulation of Mrp1-mediated transport processes, we investigated the effects of the antiviral drug ritonavir on cultured rat primary astrocytes. Ritonavir strongly stimulated the Mrp1-mediated export of glutathione (GSH) by decreasing the Km value from 200 nmol/mg to 28 nmol/mg. In contrast, ritonavir decreased the export of the other Mrp1 substrates glutathione disulfide (GSSG) and bimane-glutathione. To give explanation for these apparently contradictory observations, we performed in silico docking analysis and molecular dynamics simulations using a homology model of rat Mrp1 to predict the binding modes of ritonavir, GSH and GSSG to Mrp1. The results suggest that ritonavir binds to the hydrophilic part of the bipartite binding site of Mrp1 and thereby differently affects the binding and transport of the Mrp1 substrates. These new insights into the modulation of Mrp1-mediated export processes by ritonavir provide a new model to better understand GSH-dependent detoxification processes in brain cells | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Astrocyte | |
| 650 | 4 | |a Glutathione | |
| 650 | 4 | |a Molecular Dynamics Simulation | |
| 650 | 4 | |a Mrp1 | |
| 650 | 4 | |a Ritonavir¸ Transport | |
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| 700 | 1 | |a Waespy, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Ciacchi, Lucio Colombi |e verfasserin |4 aut | |
| 700 | 1 | |a Dringen, Ralf |e verfasserin |4 aut | |
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