Zhou Zhi Dong, Lim Tit Meng
Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, Singapore, 117543.
Neurochem Res. 2009 Feb;34(2):316-26. doi: 10.1007/s11064-008-9778-6. Epub 2008 Jul 5.
In this study, new procedure with improved tandem HPLC plus ESI-MS was utilized to decipher the protective role of glutathione (GSH) against dopamine (DA) oxidation. We demonstrated that auto-oxidation of DA could produce aminochrome (AM, a cyclized DA quinone), which could be effectively abrogated by reductants, especially by GSH. Furthermore GSH was demonstrated to be able to conjugate with AM to form various conjugates via condensation reactions without enzymatic catalysis. The GSH-AM conjugates tend to aggregate, possibly mediated by conjugated AM structures, but could be inhibited by GSH. We hypothesized that proteins conjugated by AM might facilitate Lewy body formation of Parkinson's disease (PD) in dopaminergic neurons via similar polymerization. We proposed that GSH could protect dopaminergic neurons against DA-induced toxicity via various mechanisms. The imbalance between DA oxidation and GSH protective capacity could be a key factor contributing to PD. Strategies to use GSH analogues, GSH inducers or to control DA oxidation might work to control PD onset and development.
在本研究中，采用改进的串联高效液相色谱法（HPLC）结合电喷雾电离质谱法（ESI-MS）的新方法来解读谷胱甘肽（GSH）对多巴胺（DA）氧化的保护作用。我们证明，DA的自氧化可产生氨基chrome（AM，一种环化的DA醌），还原剂尤其是GSH可有效消除这种物质。此外，已证明GSH能够与AM结合，通过缩合反应形成各种缀合物，且无需酶催化。GSH-AM缀合物倾向于聚集，可能由共轭AM结构介导，但可被GSH抑制。我们推测，由AM共轭的蛋白质可能通过类似的聚合作用促进帕金森病（PD）中多巴胺能神经元路易小体的形成。我们提出，GSH可通过多种机制保护多巴胺能神经元免受DA诱导的毒性。DA氧化与GSH保护能力之间的失衡可能是导致PD的关键因素。使用GSH类似物、GSH诱导剂或控制DA氧化的策略可能有助于控制PD的发病和发展。
