Metabolism of [14C]MPTP in mouse and monkey implicates MPP+, and not bound metabolites, as the operative neurotoxin.
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.
Yang
S C
SC
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892.
Johannessen
J N
JN
Markey
S P
SP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism* / Q000493:pharmacokinetics; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000378:metabolism; D005260:Female; D020267:MPTP Poisoning; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009498:Neurotoxins / Q000633:toxicity*; D011865:Radioisotope Dilution Technique; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium