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.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D007477:Ions; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010293:Pargyline / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000378:metabolism*; D051381:Rats
D007477:Ions; D011725:Pyridines; D011726:Pyridinium Compounds; D000255:Adenosine Triphosphate; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine