Properties and reaction of tryptamine-4,5-dione with glutathione and central toxicity and potential mechanisms of action of their reaction product 7-S-glutathionyl-tryptamine-4,5-dione

At physiological pH tryptamine-4,5-dione (1), a potentially aberrant metabolite of 5-hydroxytryptamine (5-HT) involved in the etiology of Alzheimer's disease, reacts rapidly with glutathione (GSH) to give 7-S-glutathionyl-tryptamine-4,5-dione (2). A procedure has been devised to isolate 2 and to elucidate its molecular structure using FAB-MS, ;In the presence of oxygen and excess GSH, the redox cycling between 2 and 3 leads to the depletion of oxygen and GSH and the formation of hydrogen peroxide and GSSG. Under these conditions 2 also underwent nulceophilic reaction with GSH to give arylation product and Schiff base derivatives. Some of these compounds have been isolated and their molecular structures have been elucidated using FAB-MS, ;Compound 2 exerts a remarkable catalytic effect on the redox reactions between molecular oxygen and intracellular reductants, ascorbate and NADPH. The redox cycling reaction of 2 results in the facile consumption of these reductants and formation of large amount of hydrogen peroxide. However, 2 is more likely to undergo nucleophilic reaction with cysteine. The possible roles concerning the ability of 2 to redox cycle and to react with sulfhydryl and amino groups containing compounds in the toxicity of 2 are discussed.