Oxidation of 4‐Methylcatechol: Implications for Dopamine Oxidation and Parkinson's Disease

Abstract

Dopamine oxidation may be a contributing factor in the death of dopaminergic neurons leading to Parkinson's disease. Like all catechols, dopamine oxidizes to an o-quinone especially at high pH. The dopamine side chain then inserts into the catechol ring forming a bicyclic compound, dopaminochrome. This process leads to polymerization and the formation of neuromelanin. Cyclization of the side chain, however, prevents the dopamine quinone from participating in other reactions leading to potentially more toxic products. We have studied these using 4-methyl catechol, a dopamine analogue that lacks the side-chain amine required for cyclization. 4-Methyl catechol oxidizes in solution and adds H2O to form 4-methyl 1,2,5-trihydroxybenzene. This consumes O2 but is not inhibited by superoxide dismutase. Because the reduction potential of 4-methylcatechol is too high to reduce O2 to superoxide, O2is most likely reduced by the 4-methyl catechol semiquinone formed by comproportionation of methylcatechol and the methylcatechol quinone. In the presence of aniline, 4-methyl catechol oxidizes more rapidly, and this process is inhibited by superoxide dismutase. Aniline reacts quickly with the 4-methylcatechol quinone, eliminating it and halting formation of the semiquinone by comproportionation. Thus, methylcatechol oxidation in the presence of aniline requires superoxide. Superoxide is probably generated by reaction of the methylcatechol-aniline adduct with O2. These results suggest that cyclization of the dopamine quinone prevents the formation of other products such as 6-hydroxydopamine, the adduct formed by H2O addition, and also the comproportionation of dopamine, which would facilitate oxidation. Processes that interfere with cyclization of the dopamine quinone, therefore, may increase the formation of toxic oxidative products from dopamine.