Zhang F, Dryhurst G
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019-0370.
J Med Chem. 1994 Apr 15;37(8):1084-98. doi: 10.1021/jm00034a006.
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)
在生理pH值下，儿茶酚胺能神经递质多巴胺（1）的氧化通常会导致黑色不溶性黑色素聚合物的形成。在本研究中，已证明L-半胱氨酸（CySH）可通过清除1的直接邻醌氧化产物来改变黑色素生成途径，生成5-S-半胱氨酰多巴胺（8）。在游离CySH存在下，这种半胱氨酰共轭物会进一步氧化，生成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）共轭物以及许多其他未鉴定的化合物。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更容易氧化。随着CySH摩尔过量的增加，黑色素的形成减少，最终完全被阻断。初步实验表明，当注射到实验室小鼠脑中时，二氢苯并噻嗪11及其半胱氨酰共轭物12和14具有致死性，并引发包括多动和震颤在内的深刻行为反应。基于这些结果和其他近期观察，提出了一个新的假说，这可能有助于解释特发性帕金森病（PD）中黑质纹状体多巴胺能神经元的选择性变性。该假说提出，响应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）向黑质致密部（SN）多巴胺能细胞体细胞质中的转运速率增加。这项体外研究的结果预测，GSH向色素沉着严重的多巴胺能神经元的这种升高的转运将导致神经黑色素生成途径的改变，从而使这些细胞色素脱失并形成8，所有这些都发生在帕金森病的SN中。在神经元内条件下，即神经黑色素色素沉着的细胞中，1会自动氧化，8必然会进一步非常容易地氧化，这将导致二氢苯并噻嗪11及其半胱氨酰共轭物的形成，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易于自动氧化被认为是导致在变性和帕金森病的SN中发现这种共轭物水平较低的原因。（摘要截于400字）
