The antiretroviral protease inhibitors indinavir and nelfinavir stimulate Mrp1-mediated GSH export from cultured brain astrocytes.
Combinations of antiretroviral drugs are successfully used for the treatment of acquired immune deficiency syndrome and reduce the incidence of severe human immunodeficiency virus (HIV)-associated dementia. To test whether such drugs affect the GSH metabolism of brain cells, we have exposed astrocyte-rich primary cultures to various antiretroviral compounds. Treatment of the cultures with the protease inhibitors indinavir or nelfinavir in low micromolar concentrations resulted in a time- and concentration-dependent depletion of cellular GSH from viable cells which was accompanied by a matching increase in the extracellular GSH content. In contrast, the reverse transcriptase inhibitors zidovudine, lamivudine, efavirenz or nevirapine did not alter cellular or extracellular GSH levels. Removal of indinavir from the medium by washing the cells terminated the stimulated GSH export immediately, while the nelfinavir-induced accelerated GSH export was maintained even after removal of nelfinavir. The stimulation of the GSH export from viable astrocytes by indinavir or nelfinavir was completely prevented by the application of MK571, an inhibitor of the multidrug resistance protein 1. These data demonstrate that indinavir and nelfinavir stimulate multidrug resistance protein 1-mediated GSH export from viable astrocytes and suggest that treatment of patients with such inhibitors may affect the GSH homeostasis in brain.
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Maria
M
Brandmann
Ketki
K
Tulpule
Maike M
MM
Schmidt
Ralf
R
Dringen
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D019469:Indinavir / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D019888:Nelfinavir / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology
D005947:Glucose; D005978:Glutathione; D017320:HIV Protease Inhibitors; D006861:Hydrogen Peroxide; D019469:Indinavir; D019344:Lactic Acid; D020024:Leukotriene Antagonists; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019888:Nelfinavir; D011422:Propionates; D011804:Quinolines; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors; C059141:verlukast; C421109:multidrug resistance-associated protein 1