3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells
3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells
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DOI：
10.1016/s0006-8993(00)02309-x
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发表时间：
2000-06-23
期刊：
影响因子：
2.9
通讯作者：
Kopin, IJ
中科院分区：
文献类型：
--
作者：
Lamensdorf, I;Eisenhofer, G;Kopin, IJ
3，4-二羟基苯乙醛(DOPAL)是多巴胺氧化脱氨生成的一种有毒代谢物。该醛主要被乙醛脱氢酶(ALDH)氧化为3，4-二羟基苯乙酸(DOPAC)，但也被醛或醛糖还原酶(ARs)部分还原为3，4-二羟基苯乙醇(DOPET)。在以前的研究中，我们发现鱼藤酮，一种复杂的I抑制剂，可以诱导培养的PC12细胞培养上清液中DOPAL和DOPET的快速积累。在这里，我们研究了DOPAL在复合体I抑制PC12细胞毒性中的潜在作用，并比较了鱼藤酮对DOPAL和DOPET浓度的影响与MPP+的影响。鱼藤酮使DOPAL和DOPET水平升高，MPP+则使DOPAL和DOPET水平降低。大豆苷元对ALDH的抑制减少了DOPAC的形成，增加了DOPAL的积累。抑制ARs(与AL1576一起)可减少DOPET的形成和增加DOPAL浓度。联合应用ALDH和ARs可显著增加DOPAL浓度，降低DOPET和DOPAC水平。ALDH和ARS联合抑制引起的DOPAL水平升高对细胞活力无明显影响。然而，联合抑制ALDH和Ars可增强鱼藤酮的毒性。用Clorgyline抑制单胺氧化酶对鱼藤酮的毒性增强和DOPAL水平的升高均被阻断，说明在ALDH和ARs联合抑制后，DOPAL的积累是鱼藤酮毒性增强的原因。由于复合体I功能障碍被报道与帕金森病的发病机制有关，DOPAL增强复合体I抑制的有害效应可能导致多巴胺能神经元对损伤的特异性易感性。(C)2000 Elsevier Science B.V.保留所有权利。
3,4-Dihydroxyphenylacetaldehyde (DOPAL) is a toxic metabolite formed by the oxidative deamination of dopamine. This aldehyde is mainly oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH), but is also partly reduced to 3,4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase (ARs). In a previous study, we found that rotenone, a complex I inhibitor, induced a rapid accumulation of DOPAL and DOPET in the medium of cultured PC12 cells. Here, we examined the potential role of DOPAL in the toxicity induced by complex I inhibition in PC12 cells and compared the effects of rotenone on concentrations of DOPAL and DOPET to those of MPP+. DOPAL and DOPET levels were increased by rotenone but decreased by MPP+. Inhibition of ALDH by daidzein reduced the formation of DOPAC and increased the accumulation of DOPAL. Inhibition of ARs (with AL1576) diminished DOPET formation and elevated DOPAL concentrations. Combined inhibition of ALDH and ARs markedly elevated DOPAL concentrations while diminishing DOPET and DOPAC levels. The elevation of DOPAL levels induced by combined inhibition of ALDH and ARs had no effect on cell viability. However, combined inhibition of ALDH and ARs potentiated rotenone-induced toxicity. Both the potentiation of toxicity and, the increase in DOPAL levels were blocked by inhibition of monoamine oxidase with clorgyline indicating that accumulation of DOPAL was responsible for the potentiated rotenone-induced toxicity following combined inhibition of ALDH and ARs. Since complex I dysfunction is reported to be involved in the pathogenesis of Parkinson's disease, DOPAL potentiation of the deleterious effects of complex I inhibition may contribute to the specific vulnerability of dopaminergic neurons to injury. (C) 2000 Elsevier Science B.V. All rights reserved.