Metabolism of [14C]MPTP in mouse and monkey implicates MPP+ and not bound metabolites as the operative neurotoxin

Abstract

The distribution, identification, and binding of [phenyl-14C]- or [methyl-14C]MPTP metabolites have been determined in brains of mouse and monkey exposed to toxic doses of MPTP. The distribution of radiolabeled metabolites was heterogeneous, with levels of MPP+ 1-100 mumol/L in dissected and homogenized monkey brain tissues. MPP+ constituted greater than 98% of all tissue radioactivity remaining at 1-3 days in the monkey and was identified in both cortical and striatal tissue. The relevance of the 2% of unextractable ("bound") radiolabeled metabolite was assessed in mouse brain by using pargyline or mazindol pretreatments which block dopamine depletion. The amount of binding increased rather than decreased when [phenyl-14C]MPTP was used along with pargyline or mazindol but was unchanged when [methyl-14C]MPTP was employed. This demonstrates that bound metabolites are inversely correlated to neurotoxicity as well as being N-demethylated. Two extractable metabolites, demethylated MPTP (PTP) and 1-methyl-4-phenyl-2-pyridone, were found at 30-min survival times in mouse brain and probably derive from peripheral metabolism of MPTP. At 4 h, mouse brain profiles of extractable metabolites resembled those from monkey brain, containing MPP+ as the predominant (greater than 90%) constituent. The similarity of MPP+ concentrations in mouse and monkey brain homogenates with those concentrations of MPP+ known to produce biological effects in vitro, along with the inverse relationship between bound metabolites and neurotoxicity, supports the intermediacy of MPP+ as the operative neurotoxin.