Metabolism of ( sup 14 C) MPTP in mouse and monkey implicates MPP sup + , and not bound metabolites, as the operative neurotoxin

Journal Article · · Chemical Research in Toxicology; (USA)

OSTI ID:5084437

Yang, Songcheng; Johannessen, J N; Markey, S P ^[1]

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1. National Institute of Mental Health, Bethesda, MD (USA)

The distribution, identification, and binding of (phenyl-{sup 14}C)- or (methyl-{sup 14}C)MPTP metabolites have been determined in brains of mouse and monkey exposed to toxic doses of MPTP. The distribution of radiolabeled metabolites was heterogeneous, with levels of MPP{sup +} 1-100 {mu}mol/L in dissected and homogenized monkey brain tissue. MPP{sup +} constituted >98% of all tissue radioactivity remaining at 1-3 days in the monkey and was identified in both cortical and striatal tissue. The relevance of the 2% of unextractable (bound) radiolabeled metabolite was assessed in mouse brain by using pargyline or mazindol pretreatments which block dopamine depletion. The amount of binding increased rather than decreased when (phenyl-{sup 14}C)MPTP was used along with pargyline or mazindol but was unchanged when (methyl-{sup 14}C)MPTP was employed. This demonstrates that bound metabolites are inversely correlated to neurotoxicity as well as being N-demethylated. Two extractable metabolites, demethylated MPTP (PTP) and 1-methyl-4-phenyl-2-pyridone, were found at 30-min survival times in mouse brain and probably derive from peripheral metabolism of MPTP. At 4 h, mouse brain profiles of extractable metabolites resembled those from monkey brain, containing MPP{sup +} as the predominant (>90%) constituent. The similarity of MPP{sup +} concentrations in mouse and monkey brain homogenates with those concentrations of MPP{sup +} known to produce biological effects in vitro, along with the inverse relationship between bound metabolites and neurotoxicity, supports the intermediacy of MPP{sup +} as the operative neurotoxin.

• OSTI ID: 5084437
• Journal Information: Chemical Research in Toxicology; (USA), Journal Name: Chemical Research in Toxicology; (USA) Vol. 1:4; ISSN CRTOE; ISSN 0893-228X
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
560300 -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ANTIGENS
AZINES
BIOCHEMICAL REACTION KINETICS
BODY
BRAIN
CARBON 14 COMPOUNDS
CENTRAL NERVOUS SYSTEM
DISTRIBUTION
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MATERIALS
METABOLISM
METABOLITES
MICE
MONKEYS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PRIMATES
PYRIDINES
REACTION KINETICS
RODENTS
TISSUE DISTRIBUTION
TOXIC MATERIALS
TOXICITY
TOXINS
TRACER TECHNIQUES
VERTEBRATES