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The Antiretroviral Protease Inhibitor Ritonavir Accelerates Glutathione Export from Cultured Primary Astrocytes

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Abstract

Antiretroviral protease inhibitors are a class of important drugs that are used for the treatment of human immunodeficiency virus infections. Among those compounds, ritonavir is applied frequently in combination with other antiretroviral protease inhibitors, as it has been reported to boost their therapeutic efficiency. To test whether ritonavir affects the viability and the glutathione (GSH) metabolism of brain cells, we have exposed primary astrocyte cultures to this protease inhibitor. Application of ritonavir in low micromolar concentrations did not compromise cell viability, but caused a time- and concentration-dependent loss of GSH from the cells which was accompanied by a matching increase in the extracellular GSH content. Half-maximal effects were observed for ritonavir in a concentration of 3 μM. The ritonavir-induced stimulated GSH export from astrocytes was completely prevented by MK571, an inhibitor of the multidrug resistance protein 1. In addition, continuous presence of ritonavir was essential to maintain the stimulated GSH export, since removal of ritonavir terminated the stimulated GSH export. Ritonavir was more potent to stimulate GSH export from astrocytes than the antiretroviral protease inhibitors indinavir and nelfinavir, but combinations of ritonavir with indinavir or nelfinavir did not further stimulate astrocytic GSH export compared to a treatment with ritonavir alone. The strong effects of ritonavir and other antiretroviral protease inhibitors on the GSH metabolism of astrocytes suggest that a chronic treatment of patients with such compounds may affect their brain GSH metabolism.

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Acknowledgments

The authors would like to thank the Tönjes-Vagt Stiftung for the generous financial support of this project and Ketki Tulpule (University of Bremen) for critically reading the manuscript.

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Authors and Affiliations

  1. Centre for Biomolecular Interactions Bremen, University of Bremen, P.O. Box 330440, 28334, Bremen, Germany

    Christian Arend, Maria Brandmann & Ralf Dringen

  2. Centre for Environmental Research and Sustainable Technology, Leobener Strasse, 28359, Bremen, Germany

    Maria Brandmann & Ralf Dringen

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  1. Christian Arend
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  2. Maria Brandmann
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  3. Ralf Dringen
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Correspondence to Ralf Dringen.

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Christian Arend and Maria Brandmann contributed equally to this article.

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Arend, C., Brandmann, M. & Dringen, R. The Antiretroviral Protease Inhibitor Ritonavir Accelerates Glutathione Export from Cultured Primary Astrocytes. Neurochem Res 38, 732–741 (2013). https://doi.org/10.1007/s11064-013-0971-x

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