IRON-MEDIATED GENERATION OF THE NEUROTOXIN 6-HYDROXYDOPAMINE QUINONE BY REACTION OF FATTY-ACID HYDROPEROXIDES WITH DOPAMINE - A POSSIBLE CONTRIBUTORY MECHANISM FOR NEURONAL DEGENERATION IN PARKINSONS-DISEASE

Exposure of dopamine to an excess of linoleic acid 13-hydroperoxide (1 3-hydroperoxyoctadecadienoic acid) in the presence of ferrous ions in Tris buffer, pH 7.4, resulted in a relatively fast, oxygen-independent reaction exhibiting first-order kinetics with respect to both catecho lamine and metal concentrations. Product analysis in the early stages revealed the presence of significant amounts of the quinone of the neu rotoxin 6-hydroxydopamine, together with some aminochrome and ill-defi ned melanin-like material. Quinone formation required the presence of iron, either in the ferrous or ferric form, and was unaffected by pero xidase, catalase, and hydroxyl radical scavengers, e.g. mannitol, as w ell as biologically relevant antioxidants, like ascorbate and glutathi one. Hydrogen peroxide proved as effective as linoleic acid hydroperox ide in inducing dopamine oxidation and conversion to 6-hydroxydopamine quinone. Metal chelators, including EDTA and bipyridyl, markedly supp ressed quinone formation without, however, inhibiting dopamine oxidati on. These and other results are consistent with a hydroxyl radical ind ependent hydroxylation/oxidation mechanism basically different from th e Fenton reaction, which involves direct interaction of the peroxide w ith a dopamine-Fe(III) chelate generated during the process.