Biosynthesis of N-Methylisoquinolinium Ion, a Potent Inhibitor of Catecholamine Metabolism, from 1,2,3,4-Tetrahydroisoquinoline Through N-Methyl-1,2,3,4-Tetrahydroisoquinoline in Human Brain

  • Makoto Naoi
  • Sadao Matsuura
  • Tsutomu Takahashi
  • Toshiharu Nagatsu
Part of the Advances in Behavioral Biology book series (ABBI, volume 38A)


The discovery of N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) as a neurotoxin that elicits symptoms very similar to those of parkinsonism in humans’ indicates that similar compounds may accumulate in human brain and cause neurodegeneration of the central nervous system. In human brain, 1,2,3,4-tetrahydroisoquingline (TIQ) was found and its amount was increased in a parkinsonian brain2. TIQ produced parkinsonism in primates by systemic administration, with a reduction in dopamine and biopterin contents and in the activity of tyrosine hydroxylase [TH; tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC] in the nigro-striatal region.3 Of the derivatives of TIQ, the N-methylisoquinolinium ion (NMIQ+) has a chemical structure similar to that of an oxidative product of MPTP, N-methyl-4-phenylpyridinium jon (MPP+). NMIQ+ is a potent inhibitor of TH in rat striatal slices4, and of monoamine oxidase [MAO; monoamine: oxygen oxidoreductase (deaminating), EC].5 More recently, in a rat clonal pheochromocytoma cell line, PC12h, as a model of dopaminergic neurons, NMIQ+ inhibited in vitro and in vivo activity of TH, MAO, and aromatic L-amino acid decarboxylase [aromatic L-amino acid carboxy-lyase, EC].6 These results suggest that NMIQ+ may be an endogenous inhibitor similar to MPP+. To confirm the biosynthesis of NMIQ+ from TIQ in human brain, N-methylation of TIQ was studied, using an enzyme sample prepared from human brain. This paper reports the synthesis of NMTIQ by an N-methyltransferase in human brain and its oxidation into NMIQ+ by MAO. The enzymatic studies on the two steps of reactions were discussed in relation to the effect of TIQ derivatives on catecholamine metabolism in human brain.


Human Brain Tyrosine Hydroxylase Monoamine Oxidase Methyl Transferase Pyridinium Salt 
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  1. 1.
    G. C. Davis, A. C. Williams, S. P. Markey, M. H. Ebert, E. D. Caine, C. M. Reichert, and I. J. Kopin, Chronic parkinsonism secondary to intravenous injection of meperidine analogues, Psychiat. Res. 1: 24 (1979).Google Scholar
  2. 2.
    T. Niwa, N. Takeda, N. Kaneda, Y. Hashizume, and T. Nagatsu, Presence of tetrahydroisoquinoline and 2-methyl-tetrahydroquinoline in parkinsonian and normal human brain, Biochem. Biophys. Res. Commun. 144: 1084 (1987).PubMedCrossRefGoogle Scholar
  3. 3.
    T. Nagatsu and M. Yoshida, An endogenous substance of the brain, tetrahydroisoquinoline, produces parkinsonism in primates with decreased dopamine, tyrosine hydroxylase and biopterins in the nigrostriatal regions, Neurosci. Lett. 87: 178 (1988).PubMedCrossRefGoogle Scholar
  4. 4.
    Y. Hirata, H. Sugimura, H. Takai, and T. Nagatsu, The effects of pyridinium salts, structurally related compounds of 1-methyl-4phenylpyridinium ion (MPP+), on tyrosine hydroxylation in rat striatal tissue slices, Brain Res. 397: 341 (1986).PubMedCrossRefGoogle Scholar
  5. 5.
    M. Naoi, Y. Hirata, and T. Nagatsu, Inhibition of monoamine oxidase by N-methylisoquinolinium ion, J. Neurochem. 48: 709 (1987).PubMedCrossRefGoogle Scholar
  6. 6.
    M. Naoi, T. Takahashi, H. Parvez, R. Kabeya, E. Taguchi, K. Yamaguchi, Y. Hirata, M. Minami, and T. Nagatsu, N-Methylisoquinolinium ion as an inhibitor of tyrosine hydroxylase, aromatic L-aminoacid decarboxylase, Neurochem. Int. in press. (1989).Google Scholar
  7. 7.
    M. Naoi, Y. Nomura, R. Ishiki, H. Suzuki, and T. Nagatsu, 1,4Benzoquinone as a new inhibitor of monoamine oxidase, Neurosci. Lett. 77: 215 (1987).PubMedCrossRefGoogle Scholar
  8. 8.
    M. Naoi, S. Matsuura, T. Takahashi, and T. Nagatsu, A Nmethyltransferase in human brain catalyses N-methylation of 1,2,3,4-tetrahydroisoquinoline into N-methyl-1,2,3,4tetrahydroisoquinoline, a precursor of a dopaminergic neurotoxin, N-methylisoquinolinium ion, Biochem. Biophys. Res. Commun. 161: 1213 (1989).PubMedCrossRefGoogle Scholar
  9. 9.
    M. Naoi, S. Matsuura, H. Parvez, T. Takahashi, Y. Hirata, M. Minami, and T. Nagatsu, Oxidation of N-methyl-1,2,3,4tetrahydroisoquinoline into the N-methylisoquinolinium ion by monoamine oxidase, J. Neurochem. 52: 653 (1989).PubMedCrossRefGoogle Scholar
  10. 10.
    S. S. Ansher, J. L. Cadet, W. B. Jakoby, and J. K. Baker, Role of Nmethyltransferase in the neurotoxicity associated with the metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other 4-substituted pyridines present in the environment, Biochem. Pharmacol. 35: 3359 (1986).PubMedCrossRefGoogle Scholar
  11. 11.
    T. Niwa, H. Yoshizumi, A. Tatematsu, S. Matsuura, and T. Nagatsu, Presence of tetrahydroisoquinoline, a parkinsonism-related compounds, in food, J. Chromat. 493: 347 (1989).CrossRefGoogle Scholar
  12. 12.
    T. Niwa, N. Takeda, A. Tatematsu, S. Matsuura, M. Yoshida, and T. Nagatsu, Migration of tetrahydroisoquinoline, a possible parkinsonian neurotoxin, into monkey brain from blood as proved by gas chromatography-mass spectrometry, J. Chromat. 452: 85 (1989).CrossRefGoogle Scholar
  13. 13.
    M. Naoi and T. Nagatsu, Inhibition of type A monoamine oxidase by methylquinolines and structurally related compounds, J. Neurochem. 50: 1105 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    M. V. Kindt, S. K. Youngster, P. K. Sonsalla, R. C. Duvoisin, and R. E. Heikkila, Role for monoamine oxidase-A (MAO-A) in the bioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTP analog, 2’Me-MPTP, Eur. J. Pharmacol. 146: 313 (1988).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Makoto Naoi
    • 1
  • Sadao Matsuura
    • 2
  • Tsutomu Takahashi
    • 3
  • Toshiharu Nagatsu
    • 1
  1. 1.Department of BiochemistryNagoya University School of MedicineNagoyaJapan
  2. 2.Department of Chemistry, College of General EducationNagoya UniversityJapan
  3. 3.Department of Food and NutritionKonan Women’s CollegeKonanJapan

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