Effects of L-cysteine on the oxidation chemistry of dopamine: new reaction pathways of potential relevance to idiopathic Parkinson's disease.
Effects of L-cysteine on the oxidation chemistry of dopamine: new reaction pathways of potential relevance to idiopathic Parkinson's disease.
复制标题
L-半胱氨酸对多巴胺氧化化学的影响：与特发性帕金森病潜在相关的新反应途径。
DOI：
10.1021/jm00034a006
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发表时间：
1994
影响因子：
7.3
通讯作者：
G. Dryhurst
中科院分区：
文献类型：
--
作者：
Fa Zhang;G. Dryhurst
儿茶酚胺能神经递质多巴胺 (1) 在生理 pH 值下的氧化通常会导致黑色不溶性黑色素聚合物的形成。本研究证明，L-半胱氨酸 (CySH) 可以通过清除 1 的邻醌氧化产物生成 5-S-半胱氨酰多巴胺 (8)，从而转移黑色素途径。该半胱氨酰缀合物在游离 CySH 存在下进一步氧化，得到 7-(2-氨基乙基)-3,4-二氢-5-羟基-2H-1,4-苯并噻嗪-3-羧酸 (11) 及其 6-S-半胱氨酰 (12)、8-S-半胱氨酰 (14) 和 6,8-二-S-半胱氨酰 (16) 缀合物以及许多其他未鉴定的缀合物化合物。 5-S-半胱氨酰多巴胺 (8) 和二氢苯并噻嗪 11、12、14 和 16 都比 1 更容易被氧化。随着 CySH 摩尔过量的增加，黑色素的形成减少，并最终完全阻止。初步实验表明，当注射到实验室小鼠的大脑中时，二氢苯并噻嗪 11 及其半胱氨酰缀合物 12 和 14 是致命的，并会引起严重的行为反应，包括多动和震颤。根据这些结果和其他最近的观察结果，提出了一个新的假设，该假设可能有助于解释特发性帕金森病（PD）中发生的黑质纹状体多巴胺能神经元的选择性变性。该假设提出，为了应对某种形式的慢性脑损伤，γ-谷氨酰转肽酶的活性上调，导致谷胱甘肽（GSH）转位到黑质（SN）致密旁多巴胺能细胞体细胞质中的速率增加。这项体外研究的结果预测，GSH 移位到色素重的多巴胺能神经元中的这种升高会导致神经黑色素途径的转移，从而导致这些细胞脱色并形成 8，所有这些都发生在帕金森病 SN 中。 8 的进一步非常容易的氧化必须在 1 被自动氧化的神经元内条件下发生，即在神经黑色素色素细胞中，将导致二氢苯并噻嗪 11 及其半胱氨酰缀合物，它们可能是导致 PD 中多巴胺能 SN 神经元选择性变性的内毒素。 8 的自氧化容易性被认为是在退化和帕金森 SN 中发现的这种结合物水平较低的原因。（摘要截断为 400 字）
Oxidation of the catecholaminergic neurotransmitter dopamine (1) at physiological pH normally results in formation of black, insoluble melanin polymer. In this study, it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by scavenging the proximate o-quinone oxidation product of 1 to give 5-S-cysteinyldopamine (8). This cysteinyl conjugate is further oxidized in the presence of free CySH to give 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H- 1,4-benzothiazine-3-carboxylic acid (11) and its 6-S-cysteinyl (12), 8-S-cysteinyl (14), and 6,8-di-S-cysteinyl (16) conjugates in addition to many other unidentified compounds. 5-S-Cysteinyldopamine (8) and dihydrobenzothiazines 11, 12, 14, and 16 are all more easily oxidized than 1. With increasing molar excesses of CySH, the formation of melanin is decreased and, ultimately, completely blocked. Preliminary experiments have revealed that when injected into the brains of laboratory mice, dihydrobenzothiazine 11 and its cysteinyl conjugates 12 and 14 are lethal and evoke profound behavioral responses including hyperactivity and tremor. On the basis of these results and other recent observations, a new hypothesis has been advanced which might help explain the selective degeneration of nigrostriatal dopaminergic neurons which occurs in idiopathic Parkinson's Disease (PD). This hypothesis proposes that in response to some form of chronic brain insult, the activity of gamma-glutamyltranspeptidase is upregulated leading to an increased rate of translocation of glutathione (GSH) into the cytoplasm of dopaminergic cell bodies in the substantia nigra (SN) para compacta. The results of this in vitro study predict that such an elevated translocation of GSH into heavily pigmented dopaminergic neurons would cause a diversion of the neuromelanin pathway with consequent depigmentation of these cells and formation of 8, all of which occur in the Parkinsonian SN. The further very facile oxidation of 8 which must occur under intraneuronal conditions where 1 is autoxidized, i.e., in neuromelanin-pigmented cells, would lead to dihydrobenzothiazine 11 and its cysteinyl conjugates which could be the endotoxins responsible for the selective degeneration of dopaminergic SN neurons in PD. The ease of autoxidation of 8 is suggested to account for the low levels of this conjugate found in the degenerating and Parkinsonian SN.(ABSTRACT TRUNCATED AT 400 WORDS)