Processing of MPTP by monoamine oxidases: implications for molecular toxicology

  • A. J. Trevor
  • T. P. Singer
  • R. R. Ramsay
  • N. CastagnoliJr.
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 23)


MPTP (l-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine), a selective nigrostriatal neurotoxin, is bioactivated by MAO-B (and less effectively by MAO-A) to 2,3-MPDP+ and this intermediate undergoes further oxidation to MPP+, partly through the activity of MAO forms. MPTP and its two primary metabolites are competitive inhibitors of both A and B forms of MAO. MPTP and 2,3-MPDP+ are also mechanism-based inactivators of both forms of the enzyme. A catalytic mechanism, involving the formation of radical intermediates, is proposed for the MAO-mediated oxidation of MPTP. Postoxidation biochemical sequelae, possibly involved in the expression of neurotoxicity, include the active accumulation of MPP+ via dopamine reuptake systems, the energy-driven uptake of MPP+ by mitochondria and the inhibition of NADH dehydrogenase by pyridine derivatives. A scheme linking these events as steps in the molecular mechanism of action of MPTP is proposed and discussed in terms of the selective toxicity of the neurotoxin towards nigrostriatal cells.


Monoamine Oxidase NADH Dehydrogenase Brain Mitochondrion NADH Oxidation Succinate Oxidation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Springer-Verlag/Wien 1987

Authors and Affiliations

  • A. J. Trevor
    • 1
    • 2
  • T. P. Singer
    • 1
    • 3
    • 4
  • R. R. Ramsay
    • 4
  • N. CastagnoliJr.
    • 1
    • 2
  1. 1.Department of Pharmaceutical ChemistrySan FranciscoUSA
  2. 2.Department of PharmacologySan FranciscoUSA
  3. 3.Department of Biochemistry and BiophysicsUniversity of CaliforniaSan FranciscoUSA
  4. 4.Molecular Biology DivisionVeterans Administration Medical CenterSan FranciscoUSA

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