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 aberrant oxidations of 5-HT occur in the central nervous system of individuals with Alzheimer's disease (AD). In the event that Compound 1 is formed as a result of oxidation of 5-HT within serotonergic nerve terminals or axons, it would be expected to be rapidly conjugated by intraneuronal glutathione (GSH) to give 7-S-glutathionyl-tryptamine-4,5-dione (Compound 2). When injected into the brains of laboratory mice, Compound 2 was lethal (LD50 = 21 micrograms) and evoked hyperactivity for the first 30 min following drug administration. Particularly during this hyperactive phase Compound 2 caused a statistically significant decrease in whole brain levels of norepinephrine and 5-HT. Levels of dopamine were also decreased while whole brain concentrations of its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were increased significantly. In the presence of GSH, NADPH and ascorbic acid, Compound 2 redox cycled in reactions that catalyzed the oxidation of these cellular reductants by molecular oxygen and formed H2O2 as a byproduct. Compound 2 also reacted with molar excesses of GSH to form more structurally complex glutathionyl conjugates. Several of these conjugates have been isolated and their structures determined using spectroscopic methods. It is conceivable that one or more of these conjugates might serve as analytical markers in a search for evidence in support of the hypothesis that aberrant oxidations of 5-HT occur in the Alzheimer brain. The redox cycling properties of Compound 2 and its facile reactions with cellular nucleophiles such as GSH may represent mechanisms that contribute to the toxicity of this drug.
Wong
K S
KS
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019.
Goyal
R N
RN
Wrona
M Z
MZ
Blank
C L
CL
Dryhurst
G
G
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry; D004298:Dopamine / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism*; D014363:Tryptamines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology
D014363:Tryptamines; C084237:7-S-glutathionyltryptamine-4,5-dione; D012701:Serotonin; D005978:Glutathione; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine