l-Methyl-4–phenylpyridinium (MPP+) but not 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Serves as Methyl Donor for Dopamine: A Possible Mechanism of Action

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP⁺), the active product of MPTP, caused Parkinson's disease-like symptoms. The mechanism of action of MPP⁺ is unknown, but analogues of MPTP lacking an N-methyl group were found to be essentially devoid of toxicity, which means that the methyl group of the pyridine ring plays a role in the toxicity. This is of interest because S-adenosylmethionine (SAM), which is the biologic methyl donor and requires a methyl group for its action, also caused MPP⁺-like motor deficits in rodents. Therefore, the requirement of a methyl group by MPTP and MPP⁺ for their actions suggests that, like SAM, MPP⁺ and MPTP may serve as methyl donors. This hypothesis was tested by reacting SAM, MPP⁺, or MPTP with dopamine in the presence of catechol-O-methyltransferase and measuring the methylated product of dopamine produced. Like SAM, MPP⁺, but not MPTP, methylated dopamine. The methylated product coeluted from chromatographic columns with standard 3-methox-ytyramine. Concentrations of 15.6, 62.5, 250, and 1000 nmoles/tube increased the 3-methoxytyramine recovered above controls by 0.0, 6.88, 44.55, 129.47 and 5.8, 13.9, 50.58, 121.31 nmoles for SAM and MPP⁺, respectively. The dopamine that remained unreacted was dose-dependently decreased. MPTP had no significant effect. The ability of MPP⁺ to serve as a methyl donor may represent a mechanism for the toxicity of MPP⁺. (J Geriatr Psychiatry Neurol 1992;5:114–118).