Mz. Wrona et G. Dryhurst, OXIDATION OF SEROTONIN BY SUPEROXIDE RADICAL - IMPLICATIONS TO NEURODEGENERATIVE BRAIN DISORDERS, Chemical research in toxicology, 11(6), 1998, pp. 639-650
Many new lines of evidence implicate both superoxide anion radical (O-
2 .(-)) and biogenic amine neurotransmitters in the pathological mecha
nisms that underlie neuronal damage caused by methamphetamine (MA), gl
utamate-mediated oxidative toxicity, ischemia-reperfusion, and other n
eurodegenerative brain disorders. In this investigation the oxidation
of 5-hydroxy-tryptamine (5-HT, serotonin) by an O-2 .(-)-generating sy
stem (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.
4 has been studied. The major product of the O-2 .(-)-mediated oxidati
on of 5-HT is tryptamine-4,5-dione (T-4,5-D). However, O-2 .(-) and H2
O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine
to uric acid, together react with trace levels of iron that contamina
te buffer constituents to give a chemically ill-defined ore-iron speci
es. This species mediates the oxidation of 5-HT to a C(4)-centered car
bocation intermediate that reacts with 5-HT to give 5,5'-dihydroxy-4,4
'-bitryptamine (4,4'-D) and with uric acid to give 9-[3-(2-aminoethyl)
-5-hydroxy-1H-indol-4-yl]-2,6, 8-triketo-1H, 3H, 7H-purine (7) as the
major products. These products differ from those formed in the HO.-med
iated oxidation of 5-HT under similar conditions. When the reaction is
carried out in the presence of the intraneuronal nucleophile glutathi
one (GSH), T-4,5-D is scavenged to give 7-(S-glutathionyl)-tryptamine-
4,5-dione, whereas the putative carbocation intermediate is scavenged
to give 4-(S-glutathionyl)-5-hydroxytryptamine T-4,5-D also reacts wit
h the sulfhydryl residues of a model protein, alcohol dehydrogenase, a
nd inhibits its activity. Previous investigators have proposed that T-
4,5-D is a serotonergic neurotoxin. This raises the possibility that T
-4,5-D and perhaps other putative intraneuronal metabolites formed by
the O-2 .(-)/H2O2/oxo-iron-mediated oxidations of 5-HT might be endoto
xins that contribute to neurodegeneration in brain regions innervated
by serotonergic neurons caused by MA, ischemia-reperfusion, and other
neurodegenerative brain disorders.