Metabolic studies on the nigrostriatal toxin MPTP and its MAO B generated dihydropyridinium metabolite MPDP+.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Wu
E
E
Division of Toxicology, University of California School of Pharmacy, San Francisco 94143-0446.
Shinka
T
T
Caldera-Munoz
P
P
Yoshizumi
H
H
Trevor
A
A
Castagnoli
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000378:metabolism*; D011817:Rabbits; D013378:Substantia Nigra / Q000378:metabolism*
D007527:Isoenzymes; D011726:Pyridinium Compounds; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase