N-Methylation of dopamine-derived 6,7-dihydroxyisoquinolines produces compounds whose chemical structures are similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N-Methylation of 1,2,3,4-tetrahydroisoquinoline was proved by in vitro experiments using human brain homogenate as an enzyme source. By in vivo microdialysis in rat brains, N-methylation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines (salsolinols) was also demonstrated. Among the brain regions examined, the activity of N-methylation was the highest in the substantia nigra. N-methyl-1,2,3,4-tetrahydroisoquinoline was oxidized to produce N-methyl-isoquinolinium ion by type A and type B monoamine oxidase prepared from human brain synaptosomal mitochondria. The structure of the oxidized isoquinoline is similar to that of 1-methyl-4-phenylpyridinium ion, a potent dopaminergic neurotoxin. These results indicate that these isoquinolines produced in or around dopamine neurons are N-methylated especially in substantia nigra and may be further oxidized by monoamine oxidase to produce ions. This biosynthesis pathway is quite similar to the oxidative synthesis of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. N-Methylation and oxidation of isoquinolines or other endogenous compounds may be involved in the pathogenesis of Parkinson's disease.