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Novel toxins and Parkinson’s disease: N-methylation and oxidation as metabolic bioactivation of neurotoxin

  • M. Naoi
  • W. Maruyama
  • T. Niwa
  • T. Nagatsu
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 41)

Summary

In human brains, a series of monoamine-derived 1,2,3,4-tetrahydroisoquinolines and the 6,7-dihydroxy derivatives has been identified. A tetrahydroisoquinoline was found to cause parkinsonism in monkey, but its toxicity was not so potent as 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine. Two metabolic steps were found to increase cytotoxicity of isoquinolines. N-Methylation by a non-specific N-methyltransferase was proved by in vivo and in vitro experiments. The N-methylated compound was oxidized into N-methylisoquinolinium ion by monoamine oxidase from human brain mitochondria. The oxidation was proved by microdialysis in the rat brain. The isoquinolinium ion was more cytotoxic than the two metabolic precursors. N-Methylation of dopamine-derived 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines was detected by in vivo micro-dialysis in the rat striatum, and their presence in the human brain was confirmed by GC-MS. The metabolic bioactivation may be a general pathway to produce neurotoxins as the pathogenic agents of Parkinson’s disease.

Keywords

Tyrosine Hydroxylase Monoamine Oxidase Pyridinium Salt Nagoya Institute Dopaminergic Neurotoxin 
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 1994

Authors and Affiliations

  • M. Naoi
    • 1
  • W. Maruyama
    • 2
  • T. Niwa
    • 3
  • T. Nagatsu
    • 4
  1. 1.Department of BiosciencesNagoya Institute of TechnologyShowa-ku, Gokiso-cho, Nagoya 466Japan
  2. 2.Department of NeurologyNagoya University School of MedicineNagoyaJapan
  3. 3.Department of Internal MedicineNagoya University Branch HospitalNagoyaJapan
  4. 4.Division of Molecular Genetics (II) Neurochemistry, Institute for Comprehensive Medical Science, School of MedicineFujita Health UniversityToyoakeJapan

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