title: Participation of protein kinases in cytotoxic and proapoptotic effects of ethylene glycol ethers and their metabolites in SH-SY5Y cells.
abstract: Ethylene glycol ethers (EGEs) are compounds widely used in many branches of industry. Their toxicological profile in the peripheral tissues is relatively well described, but little is known about their action on the central nervous system (CNS). In this study, we evaluated the effect of 2-ethoxyethanol (EE), 2-butoxyethanol (BE), 2-phenoxyethanol (PHE) and their metabolites on necrotic (estimated by cell viability and lactate dehydrogenase release) and apoptotic (caspase-3 activity and mitochondrial membrane potential) processes and reactive oxygen species' (ROS) production in human neuroblastoma (SH-SY5Y) cells. We have shown that, similar to the peripheral tissues, EGE metabolites in most of the performed assays revealed greater potential to damage than the parent compounds in the CNS cells. Subsequently, we investigated the participation of some selected protein kinases in the degenerative activity of PHE and its main metabolite, phenoxyacetic acid (PHA). It has been found that a GSK3β inhibitor weakened the damaging effects of PHE and PHA in each of the performed assays. Furthermore, the kinases, p38-MAPK, JNK-MAPK and PKC, had a significant role in the cytotoxic and proapoptotic effects of PHA. These results indicate that the neurotoxic effect of EGEs may stem from their impact on many intracellular signal transduction pathways.
authors: Department of Biochemical Toxicology, Chair of Toxicology, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland; Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm, Sweden. Electronic address: bartosz.pomierny@uj.edu.pl.
authors: Bartosz
authors: B
authors: Pomierny
authors: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm, Sweden. Electronic address: Kjell.Fuxe@ki.se.
authors: Kjell
authors: K
authors: Fuxe
authors: Department of Biochemical Toxicology, Chair of Toxicology, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: weronika.krzyzanowska@uj.edu.pl.
authors: Weronika
authors: W
authors: Krzyżanowska
authors: Department of Experimental Neuroendocrynology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. Electronic address: regulska@if-pan.krakow.pl.
authors: Magdalena
authors: M
authors: Regulska
authors: Department of Biochemical Toxicology, Chair of Toxicology, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: zaneta.broniowska@uj.edu.pl.
authors: Żaneta
authors: Ż
authors: Broniowska
authors: Department of Biochemical Toxicology, Chair of Toxicology, Faculty of Pharmacy, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland; Department of Experimental Neuroendocrynology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. Electronic address: boguslawa.budziszewska@uj.edu.pl.
authors: Bogusława
authors: B
authors: Budziszewska
mesh_terms: D000085:Acetates / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005026:Ethylene Glycols / Q000633:toxicity*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009336:Necrosis / Q000139:chemically induced; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012997:Solvents / Q000633:toxicity
chemical_list: D000085:Acetates; D005026:Ethylene Glycols; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D012997:Solvents; D011494:Protein Kinases; D053148:Caspase 3; C005398:phenoxyethanol; C017096:n-butoxyethanol; C021296:2-ethoxyethanol; C415326:phenoxyacetic acid
keywords: Apoptosis; Ethylene glycol ethers; MAP kinases; Neurotoxicity