Mutagenicity of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and its metabolites

The by-product from a "synthetic heroin" is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a chemical contaminant found to produce neurotoxicity similar to Parkinsonism in susceptible animals. MPTP and its oxidative metabolites were tested in the Salmonella mutagenicity test. Strains of Salmonella typhimurium that carry a nonsense mutation at the site of reversion detect a variety of naturally occurring and direct-acting mutagens. TA 100 is reverted by MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium species). This strain is more sensitive to MPDP+ mutagenesis than any other available strain of Salmonella and MPDP+ is considerably more mutagenic than MPTP and other oxidative metabolites including MPTP N-oxide or MPP+ (1-methyl-4-phenylpyridinium ion). Mutagenicity studies of metabolic incubates of MPTP with monoamine oxidase (MAO) suggest the involvement of metabolic bioactivation in the mutagenicity of MPTP. Since MPDP+ is generated from MPTP by MAO and since iminium ions are generated during cellular metabolism, they may make a contribution to the risk of human cancer.