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 monoam ine oxidase (MAO) A inhibitor, clorgyline, and the MAO B inhibitor, de prenyl, prior to the addition of the neurotoxicant 1-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP). Production of the 1-methyl-4-phenylp yridinium (MPP(+)) toxic metabolite was reduced to 11%, but not comple tely blocked, by MAO inhibition. This residual MPP(+) production appea red to be iron-dependent since it was decreased (30 to 50%) by iron ch elators, i.e., deferoxamine or phenanthroline, and was enhanced (by ap proximately 40%) in the presence of ADP-Fe3+. ADP-Fe3+ also enhanced t he oxidation of MPTP to MPP(+) which occurs in medium without cells. M PP(+) formation, however, was significantly slower in plain culture me dium than in astrocyte incubations pretreated with MAO inhibitors, sug gesting the involvement of cells in these iron-mediated reactions. The data indicate that oxidation via MAO is the primary but not the only pathway of MPTP bioactivation and that transition metals may contribut e to the generation of the toxic MPP(+) metabolite in biological syste ms. (C) 1995 Wiley-Liss, Inc.