Generation of the neurotoxin 6-hydroxydopamine by peroxidase/H2O2 oxidation of dopamine.
At physiological pH values, oxidation of the neurotransmitter dopamine (DA) by the peroxidase/H2O2 system leads to, besides dopaminochrome and 5,6-dihydroxyindole resulting from oxidative cyclization of dopaminequinone (DQ), significant amounts of the neurotoxin 6-hydroxydopamine (6-OHDA) in the oxidized quinonoid form (topaminequinone, TQ). Formation of TQ was shown to depend critically on the presence of hydrogen peroxide in the reaction medium and was not observed when DA oxidation was carried out using the tyrosinase/O2 system or chemical agents such as periodate or ferricyanide. These and other data suggest that, under the conditions adopted, nucleophilic attack of the hydrogen peroxide anion on DQ leading to TQ significantly competes with the intramolecular cyclization path. In line with this mechanism, the reaction course was not affected by the presence of hydroxyl radical scavengers. Peroxidase/H2O2 oxidation of the model N-acetyldopamine (1) gave, as expected, the 2-hydroxy-1,4-benzoquinone 3 in yields up to 55%, depending on the catecholamine/H2O2 mole ratio. Likewise, reaction of 4-methyl-1,2-benzoquinone (4) with hydrogen peroxide afforded 2-hydroxy-5-methyl-1,4-benzoquinone (5) in good yields. Collectively, these results would point to the possibility that intraneuronal formation of 6-OHDA is associated with an increased production of hydrogen peroxide under oxidative stress conditions.
Napolitano
A
A
Department of Organic and Biological Chemistry, University of Naples Federico II, Italy.
Crescenzi
O
O
Pezzella
A
A
Prota
G
G
D000838:Anions; D002384:Catalysis; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology; D014442:Monophenol Monooxygenase / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000737:chemistry / Q000378:metabolism*; D010544:Peroxidases / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D000838:Anions; D008345:Manganese; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D010544:Peroxidases; D014442:Monophenol Monooxygenase; D004298:Dopamine