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dc.contributorWichita State University. Department of Chemistryen_US
dc.contributor.authorSamms, Warren C.en_US
dc.contributor.authorPerera, Rohan P.en_US
dc.contributor.authorWimalasena, D. Shyamalien_US
dc.contributor.authorWimalasena, Kandategeen_US
dc.identifier.citationMolecular pharmacology. 2007 Sep; 72(3): 744-52.en_US
dc.descriptionClick on the DOI link below to access the article.en_US
dc.description.abstractWe 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.sponsorshipNINDS NIH HHSen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeuticsen_US
dc.relation.ispartofseriesMolecular pharmacologyen_US
dc.relation.ispartofseriesMol. Pharmacol.en_US
dc.subjectResearch Support, N.I.H., Extramuralen_US
dc.subjectResearch Support, U.S. Gov't, Non-P.H.S.en_US
dc.subject.meshAllyl Compounds/pharmacologyen_US
dc.subject.meshApoptosis/drug effectsen_US
dc.subject.meshBenzene Derivatives/pharmacologyen_US
dc.subject.meshCell Death/drug effectsen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Survival/drug effectsen_US
dc.subject.meshDose-Response Relationship, Drugen_US
dc.subject.meshHydrocarbons, Halogenated/chemistryen_US
dc.subject.meshOxidative Stress/drug effectsen_US
dc.subject.meshPropane/analogs & derivativesen_US
dc.subject.meshTime Factorsen_US
dc.subject.meshAllyl Compounds/toxicityen_US
dc.subject.meshBenzene Derivatives/toxicityen_US
dc.subject.meshHydrocarbons, Halogenated/pharmacologyen_US
dc.titlePerturbation of dopamine metabolism by 3-amino-2-(4'-halophenyl)propenes leads to increased oxidative stress and apoptotic SH-SY5Y cell deathen_US
dc.coverage.spacialUnited Statesen_US
dc.description.versionpeer revieweden_US
dc.rights.holderCopyright © 2007 The American Society for Pharmacology and Experimental Therapeuticsen_US

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