Iron-mediated oxidation of 3,4-dihydroxyphenylalanine to an excitotoxin.

2,4,5-Trihydroxyphenylalanine (TOPA) oxidizes in solution to form a quinone derivative that is a non-NMDA glutamatergic agonist and neurotoxin. DOPA can autoxidize in physiological solutions to form small amounts of both TOPA and TOPA quinone. We report here that this conversion can be dramatically enhanced by iron (II) alone, but more so by iron (II) in the presence of hydrogen peroxide. This conversion is of sufficient magnitude that the resulting product can elicit non-NMDA, glutamate receptor-mediated electrical responses in cultured cortical neurons isolated from rat. This finding suggests that TOPA quinone may play a role in pathological processes involving abnormal iron metabolism in catecholaminergic neurons.