Further insights into the oxidation chemistry and biochemistry of the serotonergic neurotoxin 5,6-dihydroxytryptamine.
The neurodegenerative properties of the serotonergic neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) are widely believed to result from its autoxidation in the central nervous system. The autoxidation chemistry of 5,6-DHT has been studied in aqueous solution at pH 7.2. The reaction is initiated by direct oxidation of the indolamine by molecular oxygen with resultant formation of the corresponding o-quinone 1 and H2O2. A rapid nucleophilic attack by 5,6-DHT on 1 leads to 2,7'-bis(5,6-dihydroxytryptamine) (6) which is more rapidly autoxidized than 5,6-DHT to give the corresponding diquinone 7 along with 2 mol of H2O2. The accumulation of 6 in the reaction solution during the autoxidation of 5,6-DHT despite its more rapid autoxidation indicates that diquinone 7 chemically oxidizes 5,6-DHT (2 mol) to quinone 1 so that an autocatalytic cycle is established. The H2O2 formed as a byproduct of these autoxidation reactions can undergo Fenton chemistry catalyzed by trace transition metal ion contaminants with resultant formation of the hydroxyl radical, HO., which directly oxidizes 5,6-DHT to a radical intermediate (9a/9b). This radical is directly attacked by O2 to yield quinone 1 and superoxide radical anion, O2.-, which further facilitates Fenton chemistry by reducing, inter alia, Fe3+ to Fe2+. A minor side reaction of 1 with water leads to formation of at least two trihydroxytryptamines. Diquinone 7 ultimately reacts with 6, 5,6-DHT, and perhaps trihydroxytryptamines, leading via a sequence of coupling and oxidation reactions to a black indolic melanin polymer. Enzymes such as tyrosinase, ceruloplasmin, and peroxidase and rat brain mitochondria catalyze the oxidation of 5,6-DHT to form dimer 7 and, ultimately, indolic melanin. The role of the autoxidation and the enzyme-mediated and mitochondria-promoted oxidations of 5,6-DHT in expressing the neurodegenerative properties of the indolamine are discussed.
Singh
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Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019.
Dryhurst
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D015115:5,6-Dihydroxytryptamine / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D002412:Cations; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000494:pharmacology; D004563:Electrochemistry; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D013053:Spectrophotometry; D013481:Superoxides / Q000378:metabolism
D002412:Cations; D005609:Free Radicals; D013481:Superoxides; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron; D014442:Monophenol Monooxygenase; D010100:Oxygen; D015115:5,6-Dihydroxytryptamine