Irreversible inhibition of mitochondrial complex I by 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxyli c acid (DHBT-1): a putative nigral endotoxin of relevance to Parkinson's disease.
Irreversible inhibition of mitochondrial complex I by 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxyli c acid (DHBT-1): a putative nigral endotoxin of relevance to Parkinson's disease.
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7-(2-氨基乙基)-3,4-二氢-5-羟基-2H-1,4-苯并噻嗪-3-羧酸 (DHBT-1) 对线粒体复合物 I 的不可逆抑制：一种推定的相关黑质内毒素
DOI：
10.1046/j.1471-4159.1997.69041530.x
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发表时间：
1997
影响因子：
4.7
通讯作者：
Dryhurst,G
中科院分区：
文献类型：
--
作者：
Li,H;Dryhurst,G
基于一系列证据，我们最近提出特发性帕金森病发病机制的一个非常早期的步骤可能是高水平的半胱氨酸易位进入黑质中神经黑色素色素多巴胺能细胞体。体外研究表明，这种半胱氨酸的流入会通过清除多巴胺-邻醌（多巴胺的近似自氧化产物）来转移神经黑色素通路，生成5 - S -半胱氨酸多巴胺，该多巴胺进一步氧化为7 -（2 -氨基乙基）- 3,4 -二氢- 5 -羟基- 2H - 1,4 -苯并噻嗪- 3 -羧酸（DHBT - 1）和其他半胱氨酸多巴胺和二氢苯并噻嗪。在这项研究中，研究人员证明，当与完整的大鼠脑线粒体孵育时，DHBT‐1抑制ADP刺激的苹果酸盐和丙酮酸盐的氧化（状态3或复合体I呼吸），ic50为0.80 mM。在KCN和/或NADH存在和不存在的情况下，DHBT‐1与冻融的大鼠脑线粒体孵育会导致NADH辅酶q1还原酶活性的不可逆的、时间依赖性的降低。当线粒体膜在没有KCN和NADH的情况下孵育时，需要显著降低DHBT‐1浓度才能产生这种效果。在后一种情况下，DHBT‐1对线粒体复合体I的不可逆抑制作用只能被谷胱甘肽、抗坏血酸、超氧化物歧化酶或过氧化氢酶部分阻断。总之，这些结果表明，DHBT‐1可以穿过线粒体外膜，通过一种与氧自由基介导的损伤无关的机制不可逆地抑制复合物I。DHBT - 1的形成只需要多巴胺、1 -半胱氨酸和氧化环境，这些条件可能存在于帕金森病黑质中神经黑色素着色的多巴胺能神经元的细胞质中。本研究结果提出了DHBT‐1可能是色素多巴胺能神经元特异性形成的内毒素，可导致帕金森病线粒体复合体I的不可逆损伤和黑质细胞死亡。
Based on a number of lines of evidence, we have proposed recently that a very early step in the pathogenesis of idiopathic Parkinson's disease might be elevated translocation ofl‐cysteine into neuromelanin‐pigmented dopaminergic cell bodies in the substantia nigra. In vitro studies suggest that such an influx ofl‐cysteine would divert the neuromelanin pathway by scavenging dopamine‐o‐quinone, the proximate autoxidation product of dopamine, to give 5‐S‐cysteinyldopamine, which is oxidized further to 7‐(2‐aminoethyl)‐3,4‐dihydro‐5‐hydroxy‐2H‐1,4‐benzothiazine‐3‐carboxylic acid (DHBT‐1) and other cysteinyldopamines and dihydrobenzothiazines. In this study, it is demonstrated that DHBT‐1 inhibits ADP‐stimulated oxidation of malate and pyruvate (state 3 or complex I respiration) when incubated with intact rat brain mitochondria with an IC50of ∼0.80 mM. Incubation of DHBT‐1 with freeze‐thawed rat brain mitochondria in both the presence and absence of KCN and/or NADH causes an irreversible, time‐dependent decrease of NADH‐coenzyme Q1reductase activity. Significantly lower concentrations of DHBT‐1 are necessary to cause this effect when mitochondrial membranes are incubated in the absence of KCN and NADH. The irreversible inhibition of mitochondrial complex I caused by DHBT‐1 under the latter conditions could be blocked only partially by glutathione, ascorbic acid, superoxide dismutase, or catalase. Together, these results suggest that DHBT‐1 can cross the outer mitochondrial membrane and irreversibly inhibit complex I by a mechanism that is not primarily related to oxygen radical‐mediated damage. Formation of DHBT‐1 requires only dopamine,l‐cysteine, and an oxidizing environment, conditions that may well exist in the cytoplasm of neuromelanin‐pigmented dopaminergic neurons in the parkinsonian substantia nigra. The results of this study raise the possibility that DHBT‐1 might be an endotoxin formed specifically in pigmented dopaminergic neurons that can contribute to irreversible damage to mitochondrial complex I and substantia nigra cell death in Parkinson's disease.