PMID- 17576792
OWN - NLM
STAT- MEDLINE
DCOM- 20071019
LR  - 20131121
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 72
IP  - 3
DP  - 2007 Sep
TI  - Perturbation of dopamine metabolism by 3-amino-2-(4'-halophenyl)propenes leads to 
      increased oxidative stress and apoptotic SH-SY5Y cell death.
PG  - 744-52
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-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.
FAU - Samms, Warren C
AU  - Samms WC
AD  - Department of Chemistry, Wichita State University, Wichita, Kansas, USA.
FAU - Perera, Rohan P
AU  - Perera RP
FAU - Wimalasena, D S
AU  - Wimalasena DS
FAU - Wimalasena, K
AU  - Wimalasena K
LA  - eng
GR  - NS39423/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20070618
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Allyl Compounds)
RN  - 0 (Benzene Derivatives)
RN  - 0 (Hydrocarbons, Halogenated)
RN  - T75W9911L6 (Propane)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Allyl Compounds/*pharmacology/toxicity
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Benzene Derivatives/*pharmacology/toxicity
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Dopamine/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Hydrocarbons, Halogenated/chemistry/pharmacology
MH  - Mice
MH  - Neuroblastoma/pathology
MH  - Oxidative Stress/*drug effects
MH  - Propane/*analogs & derivatives/chemistry/pharmacology
MH  - Time Factors
EDAT- 2007/06/20 09:00
MHDA- 2007/10/20 09:00
CRDT- 2007/06/20 09:00
PHST- 2007/06/20 09:00 [pubmed]
PHST- 2007/10/20 09:00 [medline]
PHST- 2007/06/20 09:00 [entrez]
AID - mol.107.035873 [pii]
AID - 10.1124/mol.107.035873 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2007 Sep;72(3):744-52. doi: 10.1124/mol.107.035873. Epub 2007 Jun 
      18.