7-S-GLUTATHIONYL-TRYPTAMINE-4,5-DIONE - A POSSIBLE ABERRANT METABOLITE OF SEROTONIN

Tryptamine-4,5-dione (Compound 1) is an in vitro oxidation product of 5-hydroxytryptamine (5-HT). Recent evidence has suggested that aberran t oxidations of 5-HT occur in the central nervous system of individual s with Alzheimer's disease (AD). In the event that Compound 1 is forme d as a result of oxidation of 5-HT within serotonergic nerve terminals or axons, it would be expected to be rapidly conjugated by intraneuro nal glutathione (GSH) to give 7-S-glutathionyl-tryptamine-4.5-dione (C ompound 2). When injected into the brains of laboratory mice, Compound 2 was lethal (LD50 = 21 mug) and evoked hyperactivity for the first 3 0 min following drug administration. Particularly during this hyperact ive phase Compound 2 caused a statistically significant decrease in wh ole brain levels of norepinephrine and 5-HT. Levels of dopamine were a lso decreased while whole brain concentrations of its metabolites, 3,4 -dihydroxyphenylacetic acid and homovanillic acid, were increased sign ificantly. In the presence of GSH, NADPH and ascorbic acid, Compound 2 redox cycled in reactions that catalyzed the oxidation of these cellu lar reductants by molecular oxygen and formed H2O2 as a byproduct. Com pound 2 also reacted with molar excesses of GSH to form more structura lly complex glutathionyl conjugates. Several of these conjugates have been isolated and their structures determined using spectroscopic meth ods. It is conceivable that one OT more of these conjugates might serv e as analytical markers in a search for evidence in support of the hyp othesis that aberrant oxidations of 5-HT occur in the Alzheimer brain. The redox cycling properties of Compound 2 and its facile reactions w ith cellular nucleophiles such as GSH may represent mechanisms that co ntribute to the toxicity of this drug.