Tryptamine-4,5-dione, a putative endotoxic metabolite of the superoxide-mediated oxidation of serotonin, is a mitochondrial toxin: possible implications in neurodegenerative brain disorders.
Tryptamine-4,5-dione, a putative endotoxic metabolite of the superoxide-mediated oxidation of serotonin, is a mitochondrial toxin: possible implications in neurodegenerative brain disorders.
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色胺-4,5-二酮是超氧化物介导的血清素氧化的一种假定的内毒素代谢物，是一种线粒体毒素：可能对神经退行性脑部疾病产生影响。
DOI：
10.1021/tx9801615
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Dryhurst,G
中科院分区：
文献类型：
--
作者：
Jiang,XR;Wrona,MZ;Dryhurst,G
The release and subsequent reuptake of 5-hydroxytryptamine (5-HT) and cytoplasmic superoxide (O2-•) generation have both been implicated as important factors associated with the degeneration of serotonergic neurons evoked by methamphetamine (MA) and cerebral ischemia-reperfusion (I-R). Such observations raise the possibility that tryptamine-4,5-dione (T-4,5-D), the major in vitro product of the O2-•-mediated oxidation of 5-HT, might be an endotoxicant that contributes to serotonergic neurodegeneration. When incubated with intact rat brain mitochondria, T-4,5-D (≤100 μM) uncouples respiration and inhibits state 3. Experiments with rat brain mitochondrial membrane preparations confirm that T-4,5-D evokes irreversible inhibition of NADH-coenzyme Q1(CoQ1) reductase and cytochromecoxidase (COX) apparently by covalently modifying key sulfhydryl (SH) residues at or close to the active sites of these respiratory enzyme complexes. Ascorbic acid blocks the inhibition of NADH-CoQ1reductase by maintaining T-4,5-D predominantly as 4,5-dihydroxytryptamine (4,5-DHT), thus preventing its reaction with SH residues. In contrast, ascorbic acid potentiates the irreversible inhibition of COX by T-4,5-D. This may be because the T-4,5-D−4,5-DHT couple redox cycles in the presence of excess ascorbate and molecular oxygen to cogenerate O2-•and H2O2that together react with trace levels of iron to form an oxo−iron complex that selectively damages COX. Thus, T-4,5-D might be an endotoxicant that, dependent on intraneuronal conditions, mediates irreversible damage to mitochondrial respiratory enzyme complexes and contributes to the serotonergic neurodegeneration evoked by MA and I-R.
