Overexpression of Cu-Zn superoxide dismutase protects neuroblastoma cells against dopamine cytotoxicity accompanied by increase in their glutathione level.
Dopamine (DA) was shown to exert toxic effects on cultured neurons through autoxidation or oxidative deamination, followed by formation of highly reactive quinone compounds and superoxide radicals. In the present study, therefore, any involvement of Cu-Zn superoxide dismutase (SOD) in DA toxicity was evaluated by transfection of Cu-Zn SOD cDNA. The transient transfection of Cu-Zn SOD cDNA inhibited the DA-induced decrease of dopaminergic neuroblastoma cells. Moreover, Cu-Zn SOD cDNA-transfection significantly increased the glutathione (GSH) level when the cells were exposed to DA. However, such Cu-Zn SOD-overexpression failed to show any protective effects against hydrogen peroxide. The Cu-Zn SOD-overexpressing cells also showed significantly higher levels of GSH upon DA exposure than did the empty vector-transfected cells. The increase in the GSH level in response to hydrogen peroxide remained almost identical in empty vector-transfected or Cu-Zn SOD-overexpressed cells. The level of GSH in DA-treated Cu-Zn SOD-overexpressing cells was 2.5-fold higher than that increased by hydrogen peroxide exposure. The catechol structure of DA molecule is probably involved in the mechanism of increasing GSH level. Furthermore, the Cu-Zn SOD-overexpressing cells inhibited the activation of caspase-3 upon DA exposure. Therefore, Cu-Zn SOD overexpression may temporarily inhibit or delay DA autoxidation and consequently increase the GSH level, which then prevents the activation of apoptotic pathway and subsequent cell death.
Haque
M Emdadul
ME
Department of Brain Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikatacho, Okayama 700-8558, Japan.
Asanuma
Masato
M
Higashi
Youichirou
Y
Miyazaki
Ikuko
I
Tanaka
Ken-ichi
K
Ogawa
Norio
N
D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D005978:Glutathione / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D013482:Superoxide Dismutase; D005978:Glutathione; D004298:Dopamine