EFFECTS OF N-METHYLMERCAPTOIMIDAZOLE ON THE DISPOSITION OF MPTP AND ITS METABOLITES IN MICE

The effects of N-methylmercaptoimidazole, an alternative substrate for flavin-containing monooxygenase, on the disposition of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolites, 1-methyl-4-phenyl-1,3-dihydropyridine (MPDP+) and 1-methyl-4-phenylpyridine (MPP+) in plasma and in brain tissues were studied in mice. Pretreatment of mice with N-methylmercaptoimidazole caused a significant (P < 0.01) increase in the plasma concentration of MPTP, whereas there was no significant change in the plasma concentrations of MPDP+ and MPP+. N-Methylmercaptoimidazole caused a significant (P < 0.01) increase in the levels of MPTP, MPDP+ and MPP+ in both the striatum and cortex. The conversion rates of MPTP to MPDP+ to MPP+ in whole brain homogenates were not affected by N-methylmercaptoimidazole. These results suggest that N-methylmercaptoimidazole increases the amount of MPTP delivered from the peripheral to the central nervous system, presumably by inhibiting MPTP N-oxygenation via the hepatic microsomal flavin-containing monooxygenase. An increased level of striatal MPP+, caused by the oxidation of more MPTP by brain monoamine oxidase, appears to be the mechanism by which the neurotoxicity of MPTP is enhanced by N-methylmercaptoimidazole. © 1990.