Inhibition of the tyrosine hydroxylase system by MPTP, 1-methyl-4-phenylpyridinium ion (MPP+) and the structurally related compounds in vitro and in vivo.
MPTP, 1-methyl-4-phenyl-pyridinium ion (MPP+) and the structurally related compounds including N-methyltetrahydroisoquinilinium ion inhibited the tyrosine hydroxylase (TH) system in tissue slices of rat striatum at 10(-5) M. Mouse striatum is more susceptible to MPTP than rat striatum. A similar degree of inhibition by MPP+ was observed in the absence or presence of 1 mM dibutyryl cyclic adenosine monophosphate (DBcAMP) which stimulated the TH system about 3-fold. The results with the structurally related compounds of MPP+ indicate that both the pyridinium and the phenyl group are required for the inhibition of the TH system in tissue slices or rat striatum. Tetrahydroisoquinoline, a pyridinium compound related to dopamine (DA), was found to decrease TH and 3,4-dihydroxyphenylacetic acid in the striatum of mice after administration at a dose of 60 mg/kg/day s.c. for 8 days. It is suggested that either tetrahydroisoquinoline or N-methyltetrahydroisoquinoline, which is a DA-related pyridinium compound, could be one of the environmental or endogenous compounds inducing Parkinson's disease.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001921:Brain / Q000187:drug effects*; D003342:Corpus Striatum; D007031:Hypothalamus / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
D007546:Isoquinolines; D011725:Pyridines; D011726:Pyridinium Compounds; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium