Biochemical Reactions Leading to Parkinsonian Symptoms Elicited by MPTP

  • Thomas P. Singer
  • Rona R. Ramsay
Part of the Advances in Behavioral Biology book series (ABBI, volume 38A)

Abstract

Expression of the neurotoxicity of MPTP and of its analogs-is initiated by a two-step oxidation of the corresponding pyridinium, catalyzed by monoamine oxidase (MAO) A or B. The initial enzymatic oxidation to the dihydropyridinium level is rapid, the second slower. Conversion of the dihydropyridinium to the pyridinium also occurs by spontaneous air oxidation and by chemical disproportionation. The latter is significant only at relatively high concentrations of the dihydropyridinium and seems to be negligible at neutral pH and concentrations of the dihydropyridinium likely to occur in vivo. A study of over 25 MPTP analogs1 has shown that, depending on the structure of the MPTP analog, oxidation is predominantly catalyzed by MAO A, or by MAO B, or both may be able to process the tetrahydropyridine. Thus, while MPTP is primarily bioactivated by the B enzyme, 2'-CH3-MPTP is rapidly oxidized by both, and 2'-Ethyl-, 2'-n-Propyl-, and 2'-Isopropyl-MPTP are poor substrates for MAO B but excellent ones for MAO A. Neurotoxicity in vivo reflects the specificities of MAO A and B. While deprenyl, the selective inhibitor of MAO B, blocks the neurotoxicity of MPTP,2,3 clorgyline, the A-selective MAO inhibitor, but not deprenyl, prevents the neurotoxic action of the 2'-Ethyl analog in black mice, and both deprenyl and clorgyline are needed to protect against 2'-Methyl-MPTP.4 It is clear that either type of MAO may play an important role in the expression of the neurotoxicity of environmental tetrahydropyridines.

Keywords

Dopamine Boron Superoxide Respiration Pyridinium 

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Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Thomas P. Singer
    • 1
  • Rona R. Ramsay
    • 1
  1. 1.Depts. of Biochemistry-Biophysics and Pharmacy University of California, San Francisco and Molecular Biology DivisionVeterans Administration Medical CenterSan FranciscoUSA

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