Bioactivation of MPTP: reactive metabolites and possible biochemical sequelae

Life Sci. 1987 Feb 23;40(8):713-9. doi: 10.1016/0024-3205(87)90298-0.


Expression of the selective nigrostriatal neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP] requires its bioactivation by MAO B which leads to the formation of potentially reactive metabolites including the 2-electron oxidation product, 1-methyl-4-phenyl-2,3-dihydropyridinium species [MPDP+] and the 4-electron oxidation product, the 1-methyl-4-phenyl pyridinium species [MPP+]. The latter metabolite accumulates in brain striatal tissues, is a substrate for dopaminergic active uptake systems and is an inhibitor of mitochondrial NADH dehydrogenase, a respiratory chain enzyme located in the inner mitochondrial membrane. In intact mitochondria this inhibition of respiration may be facilitated by active uptake of MPP+, a process dependent on the membrane electrical gradient. In considering possible mechanisms involved in the biochemical effects of MPP+, its redox cycling potential appears to be much lower than its chemical congener paraquat, based on attempted radical formation by chemical or enzymic reduction. Theoretically, a carbon-centered radical intermediate could be formed by 1-electron reduction of MPP+, or by 1-electron oxidation of 1-methyl-4-phenyl-1,2-dihydropyridine, the free base form of MPDP+. The 1-electron reduction of such a radical could form 1-methyl-4-phenyl-1,4-dihydropyridine [DHP]. Synthetic DHP is neurotoxic in C57B mice, and its administration leads to the formation of MPP+ in the brain, presumably through rapid auto-oxidation. The hydrolysis of DHP would yield 3-phenylglutaraldehyde and methylamine. Recent studies demonstrating the formation of methylamine in brain mitochondrial preparations containing MPTP support our suggestion that DHP may be a brain metabolite of MPTP.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Biological Transport
  • Biotransformation
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / physiology
  • Free Radicals
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Monoamine Oxidase / metabolism
  • Oxidation-Reduction
  • Pyridines / metabolism*
  • Pyridines / toxicity
  • Pyridinium Compounds / metabolism
  • Pyridinium Compounds / pharmacology
  • Rats
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism


  • Free Radicals
  • Pyridines
  • Pyridinium Compounds
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Monoamine Oxidase
  • 1-Methyl-4-phenylpyridinium
  • Dopamine