Molecular mechanim of cytotoxicity induced by dopamine and 6-hydroxydopamine

为了促进可能的帕金森病的神经保护策略，本研究进行了澄清多巴胺（DA），左旋多巴（L-DOPA）和6-羟基多巴胺（6-OHDA）的细胞毒性之间的生化机制的差异。DA和L-DOPA对Fe + H_2O_2诱导的DNA断裂有明显的促进作用，6-OHDA和Zn共存时DNA断裂明显，而Zn单独作用时DNA断裂不明显。DA相关化合物对铝诱导的DNA断裂有不同程度的抑制作用，表明铝的作用机制可能与其他过渡金属不同. 6-OHDA能促进铁诱导的羟自由基产生，DA和L-DOPA对铁诱导的羟自由基产生无影响;所有DA相关化合物均能抑制铜诱导的羟自由基产生. DA对铁诱导的脂质过氧化反应有轻微的抑制作用，而L-DOPA和6-OHDA对铁诱导的脂质过氧化反应无明显影响; DA、L-DOPA和6-OHDA对铜诱导的脂质过氧化反应有极强的抑制作用.过渡金属，特别是铜，对DAeregic神经元细胞系（B65）显示出细胞毒性。在DA相关化合物中，6-OHDA对B65细胞具有细胞毒性.过渡金属和6-OHDA能显著提高B65细胞超氧化物歧化酶（SOD）活性，而L-DOPA则能轻度提高SOD活性。铁和铜使B56细胞谷胱甘肽（GSH）活性略有下降，而DA和6-OHDA使GSH含量显著升高，表明DA、L-DOPA和6-OHDA与过渡金属、自由基和氧化还原态的相互作用不同，对B56细胞具有不同的细胞毒性。本研究结果为建立帕金森病的神经保护策略提供了有用的信息。

To promote possible neuroprotective strategies for Parkinson's disease, the present study was conducted to clarify differencies in biochemical mechanisms among cytotoxicites of dopamine (DA), levedopa (L-DOPA) and 6-hydroxydopamine (6-OHDA).1. DNA fragmentation induced by iron + hydrogen peroxide was extremely acclererated by DA and L-DOPA.Co-existence of 6-OHDA and zinc produed DNA fragmentation, although zinc alone did not produce DNA fragmentation. Aluminium-induced DNA fragmentation was differntly inhibited by DA-related compounds, indicating that action mechanism of alununium may be differant from those of the other transition metals.2. Production of hydroxyl radicals induced by iron was accelerated by 6-OHDA, although that was not affected by DA or L-DO PA.High production of hydroxyl radicals induced by cupper was suppressed by all DA-related compounds.3. Lipid peroxidation induced by iron was slightly inhibited by DA, but not affected by L-DOPA nor 6-OHDA.On the other hand, copper-induced lipid pereoxidation was extremely inhibited by DA, L-DOPA and 6-OHDA.4. Transition metals, especially copper, showed cytotoxicity against DAeregic neuronal cell line (B65). Among DA-related compounds, 6-OHDA showed cytotoxicity against B65 cells.5. Transition metals and 6-OHDA strongly increased superoxide dismutase (SOD) activities in B65 cells, but L-DOPA increased slightly SOD activities in those cells. Although iron and copper decreased slightly glutathione (GSH) activities, DA and 6-OHDA increased strongly GSH levels in B56 cells.Thus, DA, L-DOPA and 6-OHDA showed different cytotoxicities based on different interactions with transition metals, free radicals and redox states. The present results are useful information for establishing the neuroprotective strategies for Parkinson's disease.