title: Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit.
abstract: A decrease in GSH levels, the main redox regulator, can be observed in neurodegenerative diseases as well as in schizophrenia. In search for substances able to increase GSH, we evaluated the ability of curcumin (polyphenol), quercetin (flavonoid), and tert-butylhydroquinone (tBHQ) to up-regulate GSH-synthesizing enzymes. The gene expression, activity, and product levels of these enzymes were measured in cultured neurons and astrocytes. In astrocytes, all substances increased GSH levels and the activity of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). In neurons, curcumin and to a lesser extent tBHQ increased GCL activity and GSH levels, while quercetin decreased GSH and led to cell death. In the two cell types, the gene that showed the greatest increase in its expression was the one coding for the modifier subunit of GCL (GCLM). The increase in mRNA levels of GCLM was 3 to 7-fold higher than that of the catalytic subunit. In astrocytes from GCLM-knock-out mice showing low GSH (-80%) and low GCL activity (-50%), none of the substances succeeded in increasing GSH synthesis. Our results indicate that GCLM is essential for the up-regulation of GCL activity induced by curcumin, quercetin and tBHQ.
authors.affiliation: Department of Psychiatry, Center for Psychiatric Neuroscience, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: Suzie
authors.initials: S
authors.lastname: Lavoie
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: René
authors.initials: R
authors.lastname: Gysin
authors.forename: Michel
authors.initials: M
authors.lastname: Cuénod
authors.forename: Pascal
authors.initials: P
authors.lastname: Steullet
authors.forename: Kim Q
authors.initials: KQ
authors.lastname: Do
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003474:Curcumin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006873:Hydroquinones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics; D011794:Quercetin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D021122:Protein Subunits; D011794:Quercetin; C018855:2-tert-butylhydroquinone; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D003474:Curcumin