+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Metabolic studies on the nigrostriatal toxin MPTP and its MAO B generated dihydropyridinium metabolite MPDP+



Metabolic studies on the nigrostriatal toxin MPTP and its MAO B generated dihydropyridinium metabolite MPDP+



Chemical Research in Toxicology 1(3): 186-194



The metabolic fates of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its two-electron oxidation product, the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), have been examined in mouse brain and liver tissue fractions. Incubations of MPTP (50 microM and 1 mM) with mouse brain preparations result in the expected MAO B catalyzed formation of MPDP+. The four-electron oxidation product, the 1-methyl-4-phenyl-pyridinium species (MPP+), was the only other metabolite detected. The oxidation of 50 microM MPDP+ to MPP+ in the same preparations appears to be mediated by unidentified components present in membrane containing structures. The behavior of MPTP in mouse liver subcellular fractions is considerably more complex. NADPH-supplemented liver microsomes convert MPTP to the desmethyl and N-oxide metabolites. At high (1 mM) initial concentrations of MPTP there is evidence that NADPH-dependent, pargyline-insensitive liver microsomal enzymes also catalyze the oxidation of MPTP to MPDP+. Incubations of MPDP+ with mouse liver preparations containing the cytosolic fraction led to the rapid disappearance of the substrate and the quantitative formation of a metabolic product with mass spectral and diode array UV characteristics expected for a lactam structure. Menadione, an inhibitor of the cytosolic enzyme aldehyde oxidase, inhibits the formation of this product. Unambiguous characterization of this metabolite as 1-methyl-4-phenyl-5,6-dihydro-2-pyridone was achieved by comparison of its high-resolution 1H NMR and high-resolution EI mass spectra with the corresponding spectra of a synthetic standard.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 040683088

Download citation: RISBibTeXText

PMID: 2979730

DOI: 10.1021/tx00003a010


Related references

Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+, the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Journal of Medicinal Chemistry 28(10): 1432-1436, 1985

Characterization of a product derived from the 1 methyl 4 phenyl 2 3 dihydropyridinium ion a metabolite of the nigrostriatal toxin 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine. Journal of Organic Chemistry 54(5): 1052-1055, 1989

Mechanism of oxidation of 1-methyl-4-phenyl-3,3-dihydropyridinium (MPDP+). Basic Life Sciences 49: 781-785, 1988

Mechanism of oxidation of 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+). Biochemical and Biophysical Research Communications 144(2): 692-698, 1987

Evidence for the one-electron oxidation of 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+). Biochemical and Biophysical Research Communications 147(1): 354-360, 1987

Studies on the cytochrome P-450 catalyzed ring alpha-carbon oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Chemical Research in Toxicology 3(5): 423-427, 1990

Superoxide radical production during the autooxidation of 1 methyl 4 phenyl 2 3 dihydropyridinium mpdp positive. FASEB Journal 6(4): A1055, 1992

1-methyl-4-phenyl-2,3-dihydropyridinium is transformed by ubiquinone to the selective nigrostriatal toxin 1-methyl-4-phenylpyridinium. FEBS Letters 461(3): 196-200, 1999

Metabolic studies on the nigrostriatal toxin 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine. Sandler, Mahlstrom And R. H. Belmaker (ed.). Neurology And Neurobiology (new York), Vol. 42. Progress In Catecholamine Research, Part B: Central Aspects; Sixth International Catecholamine Symposium, Jerusalem, Israel, June 14-19, . Xxxvi 592p. Alan R. Liss, Inc: New York, New York, Usa. Illus. 93-100, 1988

Impaired mutagenic activities of MPDP(+) (1-methyl-4-phenyl-2,3-dihydropyridinium) and MPP(+) (1-methyl-4-phenylpyridinium) due to their interactions with methylxanthines. Bioorganic and Medicinal Chemistry 15(15): 5150-5157, 2007

3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro. Faseb Journal 20(14): 2496-2511, 2006

The formation of reactive intermediates in the MAO-catalyzed oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicology 49(2-3): 513-519, 1988

Mechanism based inhibition of purified monoamine oxidase b by the nigrostriatal toxin mptp 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine. Federation Proceedings 44(4): 1116, 1985

Involvement of hepatic aldehyde oxidase in conversion of 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) to 1-methyl-4-phenyl-5,6-dihydro-2-pyridone. Archives of Biochemistry and Biophysics 360(1): 93-98, 1998

Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP+ and MPP+. Journal of Neural Transmission 74(2): 75-86, 1988