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.
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© 1994 Springer-Verlag
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Naoi, M., Maruyama, W., Niwa, T., Nagatsu, T. (1994). Novel toxins and Parkinson’s disease: N-methylation and oxidation as metabolic bioactivation of neurotoxin. In: Tipton, K.F., Youdim, M.B.H., Barwell, C.J., Callingham, B.A., Lyles, G.A. (eds) Amine Oxidases: Function and Dysfunction. Journal of Neural Transmission, vol 41. Springer, Vienna. https://doi.org/10.1007/978-3-7091-9324-2_26
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DOI: https://doi.org/10.1007/978-3-7091-9324-2_26
Publisher Name: Springer, Vienna
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