Novel toxins and Parkinson's disease: N-methylation and oxidation as metabolic bioactivation of neurotoxin.
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-tetrahydropyridine. 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 microdialysis 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.
Naoi
M
M
Department of Biosciences, Nagoya Institute of Technology, Japan.
Maruyama
W
W
Niwa
T
T
Nagatsu
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002452:Cell Count / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008745:Methylation; D017551:Microdialysis; D009498:Neurotoxins / Q000378:metabolism*; D010084:Oxidation-Reduction; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution
D007546:Isoquinolines; D009498:Neurotoxins; D000255:Adenosine Triphosphate