Lamensdorf I, Eisenhofer G, Harvey-White J, Nechustan A, Kirk K, Kopin I J
Clinical Neuroscience Branch, NINDS, Building 10, Room 6N252, 10 Center Drive, MSC 1620, National Institutes of Health, Bethesda, MD 20892-1620, USA.
Brain Res. 2000 Jun 23;868(2):191-201. doi: 10.1016/s0006-8993(00)02309-x.
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.
3,4 - 二羟基苯乙醛（DOPAL）是多巴胺经氧化脱氨形成的一种有毒代谢产物。这种醛主要通过醛脱氢酶（ALDH）氧化为3,4 - 二羟基苯乙酸（DOPAC），但也有一部分被醛或醛糖还原酶（ARs）还原为3,4 - 二羟基苯乙醇（DOPET）。在之前的一项研究中，我们发现鱼藤酮（一种复合体I抑制剂）能诱导培养的PC12细胞培养基中DOPAL和DOPET快速积累。在此，我们研究了DOPAL在PC12细胞中复合体I抑制所诱导的毒性中的潜在作用，并比较了鱼藤酮对DOPAL和DOPET浓度的影响与1 - 甲基 - 4 - 苯基吡啶离子（MPP⁺）的影响。鱼藤酮使DOPAL和DOPET水平升高，而MPP⁺则使其降低。大豆苷元对ALDH的抑制减少了DOPAC的形成并增加了DOPAL的积累。（用AL1576）抑制ARs减少了DOPET的形成并提高了DOPAL浓度。联合抑制ALDH和ARs显著提高了DOPAL浓度，同时降低了DOPET和DOPAC水平。ALDH和ARs联合抑制所诱导的DOPAL水平升高对细胞活力没有影响。然而，ALDH和ARs联合抑制增强了鱼藤酮诱导的毒性。用氯吉兰抑制单胺氧化酶可阻断毒性增强和DOPAL水平升高，这表明DOPAL的积累是ALDH和ARs联合抑制后鱼藤酮诱导的毒性增强的原因。由于据报道复合体I功能障碍与帕金森病的发病机制有关，DOPAL增强复合体I抑制的有害作用可能导致多巴胺能神经元对损伤的特异性易感性。
