Mechanism of metal-mediated DNA damage and apoptosis induced by 6-hydroxydopamine in neuroblastoma SH-SY5Y cells.
6-Hydroxydopamine (6-OHDA) is a neurotoxin to produce an animal model of Parkinson's disease. 6-OHDA increased the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG), a biomarker of oxidatively damaged DNA, and induced apoptosis in human neuroblastoma SH-SY5Y cells. Iron or copper chelators inhibited 6-OHDA-induced 8-oxodG formation and apoptosis. Thus, iron and copper are involved in the intracellular oxidatively generated damage to DNA, a stimulus for initiating apoptosis. This study examined DNA damage caused by 6-OHDA plus metal ions using (32)P-5'-end-labelled DNA fragments. 6-OHDA increased levels of oxidatively damaged DNA in the presence of Fe(III)EDTA or Cu(II). Cu(II)-mediated DNA damage was stronger than Fe(III)-mediated DNA damage. The spectrophotometric detection of p-quinone and the scopoletin method showed that Cu(II) more effectively accelerated the 6-OHDA auto-oxidation and H(2)O(2) generation than Fe(III)EDTA. This study suggests that copper, as well as iron, may play an important role in 6-OHDA-induced neuronal cell death.
Kobayashi
Hatasu
H
Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
Oikawa
Shinji
S
Umemura
So
S
Hirosawa
Iwao
I
Kawanishi
Shosuke
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D004249:DNA Damage; D053938:DNA Fragmentation; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity*; D013997:Time Factors
D016227:Benzoquinones; D015415:Biomarkers; D002614:Chelating Agents; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; C004532:quinone; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D007501:Iron; D003849:Deoxyguanosine