Role of N-methyltransferases 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

Abstract

Amine N-methyltransferases in the brains of humans, monkeys, mice, rabbits and rats, as well as two homogeneous enzymes isolated from rabbit liver, are capable of N-methylating 4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenyltetrahydropyridine (MPTP), and 4-phenylpyridine to 1-methyl-4-phenylpyridinium ion (MPP+). The product in each instance is a neurotoxin. The suggestion is offered that the known long half-life of methylpyridinium compounds in brain may be due to limitations in transport of such charged metabolites out of this tissue and to metabolic recycling of the desmethyl species by amine N-methyltransferases. The methylation of pyridines to quaternary amines is suggested as a means by which lipophilic compounds, having gained entrance to the cell, are converted to charged species that efflux much less readily.