Synthesis, redox properties, in vivo formation, and neurobehavioral effects of N-acetylcysteinyl conjugates of dopamine: possible metabolites of relevance to Parkinson's disease.
Synthesis, redox properties, in vivo formation, and neurobehavioral effects of N-acetylcysteinyl conjugates of dopamine: possible metabolites of relevance to Parkinson's disease.
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多巴胺 N-乙酰半胱氨酰缀合物的合成、氧化还原特性、体内形成和神经行为效应：与帕金森病相关的可能代谢物。
DOI：
10.1021/tx960052v
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Dryhurst,G
中科院分区：
文献类型：
--
作者：
Shen,XM;Xia,B;Wrona,MZ;Dryhurst,G
在特发性帕金森病(PD)的发病机制中，一个非常早期的事件被认为是半胱氨酸(CySH)和/或谷胱甘肽(GSH)移位到黑质(SN)的有色多巴胺能细胞体中，在这个过程中，细胞质中的多巴胺(DA)通常被自氧化为DA-邻苯二酚，这是导致黑色神经黑素聚合物的反应的第一步。这种高水平的谷胱甘肽和谷胱甘肽的内流可能分别导致5-S-半胱氨酸多巴胺(5-S-半胱氨酸多巴胺)和5-S-谷胱甘肽基多巴胺(5-S-谷胱甘肽-DA)的形成，并可能是帕金森病脑内谷胱甘肽的大量不可逆丧失和黑质细胞的进行性脱色的原因。然而，在帕金森病患者的大脑中没有检测到5-S-谷氨酸-DA。此外，PD患者SN和脑脊液中5-S-CyS-DA/DA和5-S-CyS-DA/高香草酸浓度比值分别显著升高，但5-S-CyS-DA的绝对浓度极低，与年龄匹配的对照组相近。对这些观察结果的一种解释是，5-S-半胱氨酸-DA可能在神经元内被氧化成更复杂的半胱氨基多巴胺以及一些二氢苯并噻嗪(DHBT)和苯并噻嗪(BTS)。类似地，5-S-谷氨酸-DA可能被神经元内氧化成更复杂的谷胱甘肽多巴胺。本研究证明，在γ-谷氨酰转氨酶(γ-GT)和半胱氨酸偶联N-乙酰转移酶的作用下，5-S-谷氨酸-DA在大鼠脑内迅速代谢为5-S-半胱氨酸-DA和5-S-(N-乙酰半胱氨基)多巴胺(5)。同样，5-S-半胱氨酸-DA在大鼠脑内代谢为5-，但比5-S-谷氨酸-DA慢。这些反应最快发生在中脑，这是一个包含SN的区域。此外，5，2-S-(N-乙酰半胱氨基)多巴胺(6)和2，5-二S(N-乙酰半胱氨基)多巴胺(9)对小鼠脑内的LD50值分别为14、25和42μg，并引起严重的多动综合征。这些结果提示，帕金森病患者SN组织和脑脊液中5-S-Glu-DA的缺失和5-S-Cys-DA的极低水平可能与它们的神经元内氧化和神经元外代谢DA的乙酰半胱氨酸结合物有关。此外，5，6和9引起的毒性特性和神经行为反应增加了DA的N-乙酰半胱氨基偶联物，除了某些半胱氨基多巴胺，DHBT和BTS，可能还包括内毒素，导致PD中SN细胞死亡和其他神经元损伤。报道了几种DA的N-乙酰半胱氨酸偶联物的合成方法，并用循环伏安法研究了它们的氧化还原行为。
A very early event in the pathogenesis of idiopathic Parkinson's disease (PD) has been proposed to be an elevated translocation ofl-cysteine (CySH) and/or glutathione (GSH) into pigmented dopaminergic cell bodies in the substantia nigra (SN) in which cytoplasmic dopamine (DA) is normally autoxidized to DA-o-quinone as the first step in a reaction leading to black neuromelanin polymer. Such an elevated influx of CySH and GSH would be expected to initially result in formation of 5-S-cysteinyldopamine (5-S-CyS-DA) and 5-S-glutathionyldopamine (5-S-Glu-DA), respectively, and might account for the massive irreversible loss of GSH and progressive depigmentation of SN cells that occurs in the Parkinsonian brain. However, 5-S-Glu-DA has not been detected in the Parkinsonian brain. Furthermore, although the 5-S-CyS-DA/DA and 5-S-CyS-DA/homovanillic acid concentration ratios increase significantly in the SN and cerebrospinal fluid, respectively, of PD patients, the absolute concentrations of 5-S-CyS-DA are extremely low and similar to those measured in age-matched control patients. One explanation for these observations is that 5-S-CyS-DA might be intraneuronally oxidized to more complex cysteinyldopamines and a number of dihydrobenzothiazines (DHBTs) and benzothiazines (BTs). Similarly, 5-S-Glu-DA might be intraneuronally oxidized to more complex glutathionyldopamines. In this investigation, however, it is demonstrated that 5-S-Glu-DA is rapidly metabolized in rat brain to 5-S-CyS-DA and 5-S-(N-acetylcysteinyl)dopamine (5) in reactions mediated by γ-glutamyl transpeptidase (γ-GT) and cysteine conjugateN-acetyltransferase. Similarly, 5-S-CyS-DA is metabolized to5in rat brain although more slowly than 5-S-Glu-DA. These reactions occur most rapidly in the midbrain, a region that contains the SN. Furthermore,5, 2-S-(N-acetylcysteinyl)dopamine (6) and 2,5-di-S-(N-acetylcysteinyl)dopamine (9) are toxic when administered into mouse brain having LD50values of 14, 25, and 42 μg, respectively, and evoke a profound hyperactivity syndrome. These results suggest that the failure to detect 5-S-Glu-DA and the presence of only very low levels of 5-S-CyS-DA in Parkinsonian SN tissue and CSF might be related to both their intraneuronal oxidation and extraneuronal metabolism toN-acetylcysteinyl conjugates of DA. Furthermore, the toxic properties and neurobehavioral responses evoked by5,6, and9raise the possibility that theseN-acetylcysteinyl conjugates of DA, in addition to certain cysteinyldopamines, DHBTs and BTs, might include endotoxins that contribute to SN cell death and other neuronal damage that occurs in PD. Methods are described for the synthesis of severalN-acetylcysteinyl conjugates of DA, and their redox behaviors have been studied using cyclic voltammetry.