title: Consequences of a Chronic Exposure of Cultured Brain Astrocytes to the Anti-Retroviral Drug Efavirenz and its Primary Metabolite 8-Hydroxy Efavirenz.
abstract: Efavirenz is a widely prescribed non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infections. To test for potential long-term consequences of efavirenz on brain cells, cultured primary astrocytes were incubated with this substance or with its primary metabolite 8-hydroxy efavirenz for up to 7 days. Both, efavirenz and 8-hydroxy efavirenz caused time- and concentration-dependent cell toxicity and stimulated in subtoxic concentrations the glycolytic flux (glucose consumption and lactate release) in astrocytes. As 8-hydroxy efavirenz was less toxic than efavirenz and stimulated glycolysis in lower concentrations we tested for a potential hydroxylation of efavirenz to 8-hydroxy efavirenz in astrocytes. Analysis of media and cell lysates by HPLC-UV and mass spectrometry revealed that after 3 days of incubation viable astrocytes had accumulated about 17 and 7 % of the applied efavirenz and 8-hydroxy efavirenz, respectively. However, in cultures treated with efavirenz neither 8-hydroxy efavirenz nor any other known metabolite of efavirenz was detectable. These data demonstrate that cultured rat astrocytes efficiently accumulate, but not metabolize, efavirenz and 8-hydroxy efavirenz and that the observed chronic stimulation of glycolysis is mediated by both efavirenz and 8-hydroxy efavirenz.
authors.affiliation: Faculty 2 (Biology/Chemistry), Center for Biomolecular Interactions Bremen, University of Bremen, P.O. Box 330440, 28334, Bremen, Germany.|Center for Environmental Research and Sustainable Technology (UFT), University of Bremen, Bremen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Arend
authors.affiliation: Center for Environmental Research and Sustainable Technology (UFT), University of Bremen, Bremen, Germany.
authors.forename: Alica
authors.initials: A
authors.lastname: Rother
authors.affiliation: Center for Environmental Research and Sustainable Technology (UFT), University of Bremen, Bremen, Germany.|Faculty of Chemistry, Department of Environmental Analysis, University of Gdańsk, ul. Wita Stwosza 63, 80-308, Gdańsk, Poland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stolte
authors.affiliation: Faculty 2 (Biology/Chemistry), Center for Biomolecular Interactions Bremen, University of Bremen, P.O. Box 330440, 28334, Bremen, Germany. ralf.dringen@uni-bremen.de.|Center for Environmental Research and Sustainable Technology (UFT), University of Bremen, Bremen, Germany. ralf.dringen@uni-bremen.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dringen
mesh_terms: D000480:Alkynes; D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048588:Benzoxazines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001921:Brain / Q000166:cytology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D013237:Stereoisomerism
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019344:Lactic Acid; D005947:Glucose; C098320:efavirenz; C570209:8-hydroxyefavirenz
keywords: Astrocytes; Chromatography; Efavirenz; Glycolysis; HIV; Lactate