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 less than 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 less than 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.
Chiba
K
K
Division of Clinical Pharmacology, National Medical Center, Tokyo, Japan.
Horii
H
H
Kubota
E
E
Ishizaki
T
T
Kato
Y
Y
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D008297:Male; D008713:Methimazole / Q000494:pharmacology*; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011726:Pyridinium Compounds / Q000378:metabolism
D011726:Pyridinium Compounds; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; C026560:1-(4-methoxyphenyl)pyridinium; D008713:Methimazole; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006899:Mixed Function Oxygenases