PT  - JOURNAL ARTICLE
AU  - Warren C. Samms
AU  - Rohan P. Perera
AU  - D. S. Wimalasena
AU  - K. Wimalasena
TI  - Perturbation of Dopamine Metabolism by 3-Amino-2-(4′-halophenyl)propenes Leads to Increased Oxidative Stress and Apoptotic SH-SY5Y Cell Death
AID  - 10.1124/mol.107.035873
DP  - 2007 Sep 01
TA  - Molecular Pharmacology
PG  - 744--752
VI  - 72
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/72/3/744.short
4100  - http://molpharm.aspetjournals.org/content/72/3/744.full
SO  - Mol Pharmacol2007 Sep 01; 72
AB  - 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-β-monooxygenase (DβM) 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 α-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. The American Society for Pharmacology and Experimental Therapeutics