1-Methyl-4-phenyl-2,3-dihydropyridinium is transformed by ubiquinone to the selective nigrostriatal toxin 1-methyl-4-phenylpyridinium.
We have studied the interaction of coenzyme Q with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)), the real neurotoxin to cause Parkinson's disease. Incubation of MPTP or MPDP(+) with rat brain synaptosomes induced complete reduction of endogenous ubiquinone-9 and ubiquinone-10 to corresponding ubiquinols. The reduction occurred in a time- and MPTP/MPDP(+) concentration-dependent manner. The reduction of ubiquinone induced by MPDP(+) went much faster than that by MPTP. MPTP did not reduce liposome-trapped ubiquinone-10, but MPDP(+) did. The real toxin MPP(+) did not reduce ubiquinone in either of the systems. The reduction by MPTP but not MPDP(+) was completely prevented by pargyline, a type B monoamine oxidase (MAO-B) inhibitor, in the synaptosomes. The results indicate that involvement of MAO-B is critical for the reduction of ubiquinone by MPTP but that MPDP(+) is a reductant of ubiquinone per se. It is suggested that ubiquinone could be an electron acceptor from MPDP(+) and promote the conversion from MPDP(+) to MPP(+) in vivo, thus accelerating the neurotoxicity of MPTP.
Shi
H
H
Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Tokyo, Japan.
Noguchi
N
N
Xu
Y
Y
Niki
E
E
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D008081:Liposomes; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism*; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism*
D008081:Liposomes; D009498:Neurotoxins; D011726:Pyridinium Compounds; D014451:Ubiquinone; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D008995:Monoamine Oxidase; C025204:Ubiquinone Q2; C003741:ubiquinol; C030571:ubiquinone 9; D015655:1-Methyl-4-phenylpyridinium