Role of 1-methyl-4-phenylpyridinium ion formation and accumulation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity to isolated hepatocytes

The parkinsonian-inducing compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is converted by isolated hepatocytes to its primary metabolite, the 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+), and to its fully oxidized derivative, 1-methyl-4-phenylpyridinium ion (MPP+). Only the latter, however, accumulates in the cells. Incubation of hepatocytes in the presence of MPDP+ also results in the selective intracellular accumulation of MPP+. Conversion to MPP+ is more rapid and extensive after exposure to MPDP+, than with MPTP and the former is also more toxic. Addition of MPP+ itself is toxic to hepatocytes but only after a long lag period, which presumably reflects its limited access to the cell and its relatively slow intracellular accumulation. As previously shown with MPTP and MPP+, the cytotoxicity of MPDP+ is dose-dependent and is consistently preceeded by complete depletion of intracellular ATP. Similar to MPP+ but not MPTP, MPDP+ causes a comparable rate and extent of cytotoxicity and ATP loss in hepatocytes pretreated with the monoamine oxidase inhibitor pargyline. Pargyline blocks hepatocyte biotransformation of MPTP to MPP+, but it has no significant effect on MPP+ accumulation after exposure to either MPDP+ or MPP+. It is concluded that MPTP is toxic to hepatocytes via its monoamine oxidase-dependent metabolism and that MPP+ is likely to be the ultimate toxic metabolite which accumulates in the cell, causing ATP depletion and eventual cell death.