Biotransformation and neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its two-electron oxidation product, and 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP sup + ) species

Thesis/Dissertation · Sun Jan 01 04:00:00 EST 1989

OSTI ID:6870755

Wu, E Y

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) specifically destroys the nitrostriatal tract in humans and certain laboratory animals, and produces a Parkinsonian syndrome. The mechanism of cellular toxicity induced by the metabolites, however, has not been elucidated. The in vitro and in vivo metabolic behavior of MPTP and MPDP{sup +} and the possible role of factors other than MAO in determining the fate of these species was examined. Neuromelanin, which enhanced the rate of oxidation of MPDP{sup +} to MPP{sup +}, may also act as a reservoir in the substantia nigra to trap MPP{sup +} and prolong its exposure to susceptible brain neurons. Diethyldithiocarbamate (DDC), reported to increase the neurotoxic effect of MPTP in mice potentiated the formation of MPDP{sup +} from the MAO B catalyzed biotransformation of MPTP and significantly lowered brain dopamine levels in animals pretreated with DDC before MPTP administration. The ability of the dihydropyridinium species to gain access to susceptible neurons via the dopamine uptake system was assessed using the stable, 3,4-dihydro-2-methyl-9-H-indeno (2,1-c)pryidinium (DMIP{sup +}) species. DMIP{sup +}, however, proved to be a poor inhibitor of both ({sup 3}H)dopamine and ({sup 3}H)MPP{sup +} uptake.

• Research Organization: California Univ., San Francisco, CA (USA)
• OSTI ID: 6870755
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
ANIMAL CELLS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
CARDIOTONICS
CARDIOVASCULAR AGENTS
DOPAMINE
DRUGS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
METABOLISM
METABOLITES
NERVE CELLS
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHENOLS
POLYPHENOLS
PYRIDINES
SOMATIC CELLS
SYMPATHOMIMETICS
TOXICITY
TRACER TECHNIQUES
TRITIUM COMPOUNDS
UPTAKE