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.

Abstract

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 (< or = 100 microM) 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 cytochrome c oxidase (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-CoQ1 reductase 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 H2O2 that 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.

• Authors: X R Jiang, M Z Wrona, G Dryhurst
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 12 Issue 5 Pg. 429-36 (May 1999) ISSN: 0893-228X [Print] United States
• PMID: 10328753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Endotoxins
• Indolequinones
• Tryptamines
• tryptamine-4,5-dione
• Superoxides
• Serotonin
• Electron Transport Complex IV
• Ascorbic Acid

Topics

• Animals
• Ascorbic Acid (pharmacology)
• Brain Chemistry (drug effects)
• Electron Transport Complex IV (antagonists & inhibitors)
• Endotoxins (metabolism)
• In Vitro Techniques
• Indolequinones
• Male
• Mitochondria (drug effects)
• Neurodegenerative Diseases (metabolism)
• Oxidation-Reduction
• Oxygen Consumption (drug effects)
• Rats
• Rats, Sprague-Dawley
• Serotonin (metabolism)
• Superoxides (metabolism)
• Tryptamines (metabolism, toxicity)