Dopachrome and aminochrome, the oxidized metabolites of dopa and dopamine : studies on the molecular mechanisms underlying their reduction and conjugation with glutathione

Sammanfattning: Dopamine, like other catecholamines can be oxidized to the corresponding ortho-quinone, which undergoes cyclization of its amino chain to cyclized dopamine ortho-quinone (aminochrome). Both o-quinones are toxic metabolites that may contribute to neurotoxic effects of these catecholamines. The oxidation of dopamine to o-quinone is believed to be one of the causes of the neurodegenerative process of Parkinson's disease.Although it is in generally accepted that free radicals are involved in the neurodegenerative process occurring in the dopaminergic neuron system in Parkinson's disease, the exact mechanism of neurodegeneration in vivo is still unknown. However, one possible source of free radicals in the dopaminergic neuron system in the central nerve system may involve the oxidation of dopamine to the corresponding o-quinone.L-Dopa is commonly used in the clinical management of Parkinson's disease. However, this treatment becomes gradually ineffective, due either to loss of efficacy or to appearance of side-effects, probably produced by the oxidative injury generated by the oxidation of dopa or of its metabolites.We report in this study that the oxidation of dopa and dopamine to the corresponding o-quinone and the followed cyclization, at physiological pH, is not itself responsible for the formation of reactive oxygen species. In addition, we show that the reduction of cyclized o-quinones of dopamine and the subsequent autoxidation is the step in which reactive species are formed.Formation of reactive oxygen species during one- or two-electron reduction of aminochrome and dopachrome has been studied in vitro by using NADPH-cytochrome P450 reductase and DT-diaphorase, respectively. The results suggest that DT-diaphorase, SOD, catalase (glutathione peroxidase) and sulfotransferase constitute the cellular defenses against formation of reactive oxygen species during reduction of aminochrome and dopachrome.We also studied the ability of human glutathione transferases to conjugate cyclized catechol o-quinones such as aminochrome and dopachrome and found that GSTs, in particularly GST M2-2 catalyzes GSH conjugation of dopachrome and aminochrome, preventing the formation of ROS and reactive catechol metabolites. The neuroprotective role of GST M2-2 suggested in the present study is depend on the presence of the enzyme in relevants regions of the human brain, regions where cell damage is observed in diseases such as schizoprenia and Parkinson's disease.