title: Manganese-induced neurotoxicity is differentially enhanced by glutathione depletion in astrocytoma and neuroblastoma cells.
abstract: Manganese (Mn) is neurotoxic: the underlying mechanisms have not been fully elucidated. L: -Buthionine-(S,R)-sulfoximine (BSO) is an irreversible inhibitor of gamma-glutamylcysteine synthetase, an important enzyme in glutathione (GSH) synthesis. To test the hypothesis that BSO modulates Mn toxicity, we investigated the effects of treatment of U-87 or SK-N-SH cells with MnCl(2), BSO, or MnCl(2) plus BSO. We monitored cell viability using MTT assay, staining with HO-33342 to assess live and/or apoptotic cells, and staining with propidium iodide (PI) to assess necrotic cells; we also measured cellular glutathione. Our results indicate decreased viability in both cell types when treated with MnCl(2) or BSO: Mn was more toxic to SK-N-SH cells, whereas BSO was more toxic to U-87 cells. Because BSO treatment accentuated Mn toxicity in both cell lines, GSH may act to combat Mn toxicity. Thus, further investigation in oxidative stress mediated by glutathione depletion will unravel new Mn toxicity mechanism(s).
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Biomedical Research Institute, Idaho State University, Pocatello, ID 83209-8288, USA.
authors.forename: Vikas V
authors.initials: VV
authors.lastname: Dukhande
authors.forename: Gauri H
authors.initials: GH
authors.lastname: Malthankar-Phatak
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Hugus
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Daniels
authors.forename: James C K
authors.initials: JC
authors.lastname: Lai
mesh_terms: D000963:Antimetabolites / Q000633:toxicity; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D019328:Buthionine Sulfoximine / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D020149:Manganese Poisoning / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*
chemical_list: D000963:Antimetabolites; D019328:Buthionine Sulfoximine; D005978:Glutathione