Iron-mediated bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in glial cultures

Primary cultures of mouse astrocytes were treated with both the monoamine oxidase (MAO) A inhibitor, clorgyline, and the MA0 B inhibitor, deprenyl, prior to the addition of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Production of the 1-methyl-4-phenylpyridinium (MPP⁺) toxic metabolite was reduced to 11%, but not completely blocked, by MA0 inhibition. This residual MPP⁺ production appeared to be iron-dependent since it was decreased (30 to 50%) by iron chelators, i.e., deferoxamine or phenanthroline, and was enhanced (by approximately 40%) in the presence of ADP-Fe³⁺. ADP-Fe³⁺ also enhanced the oxidation of MPTP to MPP⁺ which occurs in medium without cells. MPP⁺ formation, however, was significantly slower in plain culture medium than in astrocyte incubations pretreated with MAO inhibitors, suggesting the involvement of cells in these iron-mediated reactions. The data indicate that oxidation via MA0 is the primary but not the only pathway of MPTP bioactivation and that transition metals may contribute to the generation of the toxic MPP⁺ metabolite in biological systems. © 1995 Wiley-Liss, Inc.