title: Dopamine but not l-dopa stimulates neural glutathione metabolism. Potential implications for Parkinson's and other dopamine deficiency states.
abstract: Dopamine is produced first by hydroxylalation of l-tyrosine to l-dihydroxyphenylalanine (l-dopa) and subsequently by the decarboxylation of l-dopa to dopamine catalysed by the enzymes tyrosine hydroxylase and aromatic l-amino acid decarboxylase (AADC) respectively. Reduced glutathione (GSH) acts as a major cellular antioxidant. We have investigated the role of dopamine in the control of GSH homeostasis in brain cells. The SH-SY5Y human neuroblastoma cell line was found to increase intracellular GSH levels in response to 50μM dopamine treatment. Similarly the 1321N1 human astrocytoma cell line was found to increase GSH release in response to 50μM dopamine. The same concentration of l-dopa was also found to increase intracellular GSH in SH-SY5Y cells, however when AADC was inhibited this affect was abolished. Furthermore 1321N1 cells which were found to have almost undetectable levels of AADC activity did not increase GSH release in response to 50μM l-dopa. These results suggest that at these concentrations dopamine has the potential to act as a signal for the upregulation of GSH synthesis within neuronal-like cells and for the increased trafficking of GSH from astrocytes to neurons. This effect could potentially relate to the activation of antioxidant response elements leading to the induction of phase II detoxifying enzymes including those involved in GSH synthesis and release. The inability of l-dopa to produce a similar effect when AADC was inhibited or when AADC activity was absent indicates that these effects are relatively specific to dopamine. Additionally dopamine but not l-dopa treatment led in an increase in complex I activity of the respiratory chain in SH-SY5Y cells which may be related to the effect of dopamine on GSH levels.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, UK.
authors.forename: George F G
authors.initials: GF
authors.lastname: Allen
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Ullah
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.forename: John M
authors.initials: JM
authors.lastname: Land
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
mesh_terms: D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D004298:Dopamine / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism*
chemical_list: D007980:Levodopa; D001142:Aromatic-L-Amino-Acid Decarboxylases; D005978:Glutathione; D004298:Dopamine