title: Perturbation of dopamine metabolism by 3-amino-2-(4'-halophenyl)propenes leads to increased oxidative stress and apoptotic SH-SY5Y cell death.
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.
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, Kansas, USA.
authors.forename: Warren C
authors.initials: WC
authors.lastname: Samms
authors.forename: Rohan P
authors.initials: RP
authors.lastname: Perera
authors.forename: D S
authors.initials: DS
authors.lastname: Wimalasena
authors.forename: K
authors.initials: K
authors.lastname: Wimalasena
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001555:Benzene Derivatives / Q000494:pharmacology* / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006846:Hydrocarbons, Halogenated / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D011407:Propane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000498:Allyl Compounds; D001555:Benzene Derivatives; D006846:Hydrocarbons, Halogenated; D011407:Propane; D004298:Dopamine