Oxidation of serotonin by superoxide radical: implications to neurodegenerative brain disorders.
Many new lines of evidence implicate both superoxide anion radical (O2*-) and biogenic amine neurotransmitters in the pathological mechanisms that underlie neuronal damage caused by methamphetamine (MA), glutamate-mediated oxidative toxicity, ischemia-reperfusion, and other neurodegenerative brain disorders. In this investigation the oxidation of 5-hydroxytryptamine (5-HT, serotonin) by an O2*--generating system (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.4 has been studied. The major product of the O2*--mediated oxidation of 5-HT is tryptamine-4,5-dione (T-4, 5-D). However, O2*- and H2O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine to uric acid, together react with trace levels of iron that contaminate buffer constituents to give a chemically ill-defined oxo-iron species. This species mediates the oxidation of 5-HT to a C(4)-centered carbocation 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*-mediated oxidation of 5-HT under similar conditions. When the reaction is carried out in the presence of the intraneuronal nucleophile glutathione (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 with the sulfhydryl residues of a model protein, alcohol dehydrogenase, and 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 O2*-/H2O2/oxo-iron-mediated oxidations of 5-HT might be endotoxins that contribute to neurodegeneration in brain regions innervated by serotonergic neurons caused by MA, ischemia-reperfusion, and other neurodegenerative brain disorders.
Wrona
M Z
MZ
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
Dryhurst
G
G
D000975:Antioxidants / Q000494:pharmacology; D001927:Brain Diseases / Q000209:etiology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D045563:Indolequinones; D007502:Iron Chelating Agents / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000209:etiology*; D010084:Oxidation-Reduction; D011485:Protein Binding; D012701:Serotonin / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D014363:Tryptamines / Q000378:metabolism
D000975:Antioxidants; D016166:Free Radical Scavengers; D005609:Free Radicals; D045563:Indolequinones; D007502:Iron Chelating Agents; D014363:Tryptamines; C060213:tryptamine-4,5-dione; D013481:Superoxides; D012701:Serotonin; D005978:Glutathione