Reactions of the Putative Neurotoxin Tryptamine-4,5-dione with<scp>l</scp>-Cysteine and Other Thiols

Jiang, Xiang‐Rong; Wrona, Monika Z.; Alguindigue, Susan S.; Dryhurst, Glenn

doi:10.1021/tx020084k

Cited by 15 publications

(18 citation statements)

References 48 publications

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“…For MDMA, which is neurotoxic only to 5‐HT terminals, it is believed that DA‐derived ROS are generated in 5‐HT terminals either after SERT‐mediated uptake of released DA 53 or by the synthesis of DA from tyrosine 54 . Alternatively, toxic metabolites of 5‐HT oxidation or MDMA itself can also mediate MDMA toxicity 55–57 …”

Section: Classical Aspects Of Meth and Mdma Toxicitymentioning

confidence: 99%

Amphetamine toxicities

Yamamoto

Moszczynska

Gudelsky

2010

Annals of the New York Academy of Sciences

244

136

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The drugs of abuse, methamphetamine and MDMA, produce long-term decreases in markers of biogenic amine neurotransmission. These decreases have been traditionally linked to nerve terminals and are evident in a variety of species, including rodents, nonhuman primates, and humans. Recent studies indicate that the damage produced by these drugs may be more widespread than originally believed. Changes indicative of damage to cell bodies of biogenic and nonbiogenic amine–containing neurons in several brain areas and endothelial cells that make up the blood–brain barrier have been reported. The processes that mediate this damage involve not only oxidative stress but also include excitotoxic mechanisms, neuroinflammation, the ubiquitin proteasome system, as well as mitochondrial and neurotrophic factor dysfunction. These mechanisms also underlie the toxicity associated with chronic stress and human immunodeficiency virus (HIV) infection, both of which have been shown to augment the toxicity to methamphetamine. Overall, multiple mechanisms are involved and interact to promote neurotoxicity to methamphetamine and MDMA. Moreover, the high coincidence of substituted amphetamine abuse by humans with HIV and/or chronic stress exposure suggests a potential enhanced vulnerability of these individuals to the neurotoxic actions of the amphetamines.

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Section: Classical Aspects Of Meth and Mdma Toxicitymentioning

confidence: 99%

Amphetamine toxicities

Yamamoto

Moszczynska

Gudelsky

2010

Annals of the New York Academy of Sciences

244

136

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“…Production of tryptamine-4,5-dione during inflammation is likely to have detrimental sequelae. It is known to be neurotoxic [45] and readily forms conjugates with GSH that undergo further oxidation to produce additional toxic species [41,46]. It also reacts with protein thiols and has been shown to inactivate α-oxoglutarate dehydrogenase, pyruvate dehydrogenase [20] and tryptophan hydroxylase [47] by forming adducts with these enzymes.…”

Section: Scheme 1 Reaction Of Serotonin With the Redox Intermediates mentioning

confidence: 99%

Serotonin as a physiological substrate for myeloperoxidase and its superoxide-dependent oxidation to cytotoxic tryptamine-4,5-dione

Ximenes

Maghzal

Turner

et al. 2009

Biochemical Journal

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During inflammatory events, neutrophils and platelets interact to release a variety of mediators. Neutrophils generate superoxide and hydrogen peroxide, and also discharge the haem enzyme myeloperoxidase. Among numerous other mediators, platelets liberate serotonin (5-hydroxytryptamine), which is a classical neurotransmitter and vasoactive amine that has significant effects on inflammation and immunity. In the present study, we show that serotonin is a favoured substrate for myeloperoxidase because other physiological substrates for this enzyme, including chloride, did not affect its rate of oxidation. At low micromolar concentrations, serotonin enhanced hypochlorous acid production by both purified myeloperoxidase and neutrophils. At higher concentrations, it almost completely blocked the formation of hypochlorous acid. Serotonin was oxidized to a dimer by myeloperoxidase and hydrogen peroxide. It was also converted into tryptamine-4,5-dione, especially in the presence of superoxide. This toxic quinone was produced by stimulated neutrophils in a reaction that required myeloperoxidase. In plasma, stimulated human neutrophils oxidized serotonin to its dimer using the NADPH oxidase and myeloperoxidase. We propose that myeloperoxidase will oxidize serotonin at sites of inflammation. In doing so, it will impair its physiological functions and generate a toxic metabolite that will exacerbate inflammatory tissue damage. Consequently, oxidation of serotonin by myeloperoxidase may profoundly influence inflammatory processes.

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“…Among the obtained antibodies, 1B7 mAb was further characterized. As TD is known to preferentially react with thiols [5], we prepared three types of BSA, DTT–treated BSA, NEM–treated BSA, and native BSA and the effect of free thiol on the generation of immunoreactivity by exposure of TD was examined. The relative amounts of free thiols on BSA varied depending on its type, at 9.7, 0.2, and 1 for DTT–treated BSA, NEM–treated BSA, and native BSA, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…1). In addition, the adduction of TD has been shown to generate a tryptamine-4,5-diol–protein adduct, which rapidly converts to the corresponding quinone adduct [5]. However, the molecular mechanism and biological significance of protein modification by serotonin oxidation products has not been fully investigated because of the lack of an analytical tool for detection of modification in a cell or tissue.…”

Section: Introductionmentioning

confidence: 99%

Covalent modification of cytoskeletal proteins in neuronal cells by tryptamine-4,5-dione

2014

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Serotonin, 5-hydroxytryptamine, is a systemic bioactive amine that acts in the gut and brain. As a substrate of myeloperoxidase in vitro, serotonin is oxidized to tryptamine-4,5-dione (TD), which is highly reactive with thiols. In this work, we successively prepared a monoclonal antibody to quinone-modified proteins and found that the antibody preferentially recognizes the TD–thiol adduct. Using the antibody, we observed that the chloride ion, the predominant physiological substrate for myeloperoxidase in vivo, is not competitive toward the enzyme catalyzed serotonin oxidation process, suggesting that serotonin is a plausible physiological substrate for the enzyme in vivo. Immunocytochemical analyses revealed that TD staining was observed in the cytosol of SH-SY5Y neuroblastoma cells while blot analyses showed that some cellular proteins were preferentially modified. Pull-down analyses confirmed that the cytoskeletal proteins tubulins, vimentin, and neurofilament-L were modified. When pure tubulins were exposed to micromolar levels of synthetic TD, self-polymerization was initially enhanced and then suppressed. These results suggest that serotonin oxidation by myeloperoxidase or the action of other oxidants could cause functional alteration of cellular proteins, which may be related to neurodegeneration processes or irritable bowel syndrome.

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Reactions of the Putative Neurotoxin Tryptamine-4,5-dione withl-Cysteine and Other Thiols

Cited by 15 publications

References 48 publications

Amphetamine toxicities

Amphetamine toxicities

Serotonin as a physiological substrate for myeloperoxidase and its superoxide-dependent oxidation to cytotoxic tryptamine-4,5-dione

Covalent modification of cytoskeletal proteins in neuronal cells by tryptamine-4,5-dione

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