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Perturbation of dopamine metabolism by 3-amino-2-(4'-halophenyl)propenes leads to increased oxidative stress and apoptotic SH-SY5Y cell death

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dc.contributor Wichita State University. Department of Chemistry en_US
dc.contributor.author Samms, Warren C. en_US
dc.contributor.author Perera, Rohan P. en_US
dc.contributor.author Wimalasena, D. Shyamali en_US
dc.contributor.author Wimalasena, Kandatege en_US
dc.date.accessioned 2012-02-06T17:16:53Z
dc.date.available 2012-02-06T17:16:53Z
dc.date.issued 2007-09-01 en_US
dc.identifier 17576792 en_US
dc.identifier 0035623 en_US
dc.identifier mol.107.035873 en_US
dc.identifier NS39423 en_US
dc.identifier.citation Molecular pharmacology. 2007 Sep; 72(3): 744-52. en_US
dc.identifier.issn 0026-895X en_US
dc.identifier.uri http://dx.doi.org/10.1124/mol.107.035873 en_US
dc.identifier.uri http://hdl.handle.net/10057/4360
dc.description Click on the DOI link below to access the article. en_US
dc.description.abstract We have recently characterized a series of 3-amino-2-phenyl-propene (APP) derivatives as reversible inhibitors for the bovine adrenal chromaffin granule vesicular monoamine transporter (VMAT) that have been previously characterized as potent irreversible dopamine-beta-monooxygenase (DbetaM) and monoamine oxidase (MAO) inhibitors. Halogen substitution on the 4'-position of the aromatic ring gradually increases VMAT inhibition potency from 4'-F to 4'-I, parallel to the hydrophobicity of the halogen. We show that these derivatives are taken up into both neuronal and non-neuronal cells, and into resealed chromaffin granule ghosts efficiently through passive diffusion. Uptake rates increased according to the hydrophobicity of the 4'-substituent. More importantly, these derivatives are highly toxic to human neuroblastoma SH-SY5Y but not toxic to M-1, Hep G2, or human embryonic kidney 293 non-neuronal cells at similar concentrations. They drastically perturb dopamine (DA) uptake and metabolism in SH-SY5Y cells under sublethal conditions and are able to deplete both vesicular and cytosolic catecholamines in a manner similar to that of amphetamines. In addition, 4'-IAPP treatment significantly increases intracellular reactive oxygen species (ROS) and decreases glutathione (GSH) levels in SH-SY5Y cells, and cell death is significantly attenuated by the common antioxidants alpha-tocopherol, N-acetyl-l-cysteine and GSH, but not by the nonspecific caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. DNA fragmentation analysis further supports that cell death is probably due to a caspase-independent ROS-mediated apoptotic pathway. Based on these and other findings, we propose that drastic perturbation of DA metabolism in SH-SY5Y cells by 4'-halo APP derivatives causes increased oxidative stress, leading to apoptotic cell death. en_US
dc.description.sponsorship NINDS NIH HHS en_US
dc.format.extent 744-52 en_US
dc.language.iso eng en_US
dc.publisher American Society for Pharmacology and Experimental Therapeutics en_US
dc.relation.ispartofseries Molecular pharmacology en_US
dc.relation.ispartofseries Mol. Pharmacol. en_US
dc.source NLM en_US
dc.subject Research Support, N.I.H., Extramural en_US
dc.subject Research Support, U.S. Gov't, Non-P.H.S. en_US
dc.subject.mesh Allyl Compounds/pharmacology en_US
dc.subject.mesh Animals en_US
dc.subject.mesh Apoptosis/drug effects en_US
dc.subject.mesh Benzene Derivatives/pharmacology en_US
dc.subject.mesh Cell Death/drug effects en_US
dc.subject.mesh Cell Line, Tumor en_US
dc.subject.mesh Cell Survival/drug effects en_US
dc.subject.mesh Dopamine/metabolism en_US
dc.subject.mesh Dose-Response Relationship, Drug en_US
dc.subject.mesh Hydrocarbons, Halogenated/chemistry en_US
dc.subject.mesh Mice en_US
dc.subject.mesh Neuroblastoma/pathology en_US
dc.subject.mesh Oxidative Stress/drug effects en_US
dc.subject.mesh Propane/analogs & derivatives en_US
dc.subject.mesh Time Factors en_US
dc.subject.mesh Allyl Compounds/toxicity en_US
dc.subject.mesh Benzene Derivatives/toxicity en_US
dc.subject.mesh Hydrocarbons, Halogenated/pharmacology en_US
dc.subject.mesh Propane/chemistry en_US
dc.subject.mesh Propane/pharmacology en_US
dc.title Perturbation of dopamine metabolism by 3-amino-2-(4'-halophenyl)propenes leads to increased oxidative stress and apoptotic SH-SY5Y cell death en_US
dc.type Article en_US
dc.coverage.spacial United States en_US
dc.description.version peer reviewed en_US
dc.rights.holder Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics en_US

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