Real-time monitoring of superoxide generation and cytotoxicity in neuroblastoma mitochondria induced by 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline.
The potential neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) has recently been suggested to be a causative factor in the clinical development of parkinsonian symptoms after long-term exposure to precursor compounds such as the hypnotic chloral hydrate. TaClo is known to cause cell death in dopaminergic neuronal cells, however, the pathway and mechanisms remain undefined. This study reports for the first time that TaClo promotes cytotoxicity in SH-SY5Y neuroblastoma cells within 2 hours of initial exposure. TaClo also caused superoxide production from isolated mitochondria, which was comparable in response time and magnitude to production elicited by more established respiratory inhibitors such as rotenone and antimycin A. These findings present new evidence in support of TaClo-induced neuronal death via superoxide signalling and oxidative stress.
Institute of Cellular Medicine, Newcastle University, UK.
Sarah Jayne
SJ
Boulton
Paul C
PC
Keane
Christopher M
CM
Morris
Calum J
CJ
McNeil
Philip
P
Manning
D000968:Antimycin A / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019069:Cell Respiration; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D010078:Oxazines / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014966:Xanthenes / Q000494:pharmacology
D000970:Antineoplastic Agents; D002243:Carbolines; D010078:Oxazines; D014966:Xanthenes; D012402:Rotenone; D013481:Superoxides; C067372:1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline; C005843:resazurin; D000968:Antimycin A; D042967:Electron Transport Complex I