1-Methyl-4-phenyl-2,3-dihydropyridinium is transformed by ubiquinone to the selective nigrostriatal toxin 1-methyl-4-phenylpyridinium.

Abstract

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.

• Authors: H Shi, N Noguchi, Y Xu, E Niki
• Journal: FEBS letters (FEBS Lett) Vol. 461 Issue 3 Pg. 196-200 (Nov 19 1999) ISSN: 0014-5793 [Print] England
• PMID: 10567696 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Liposomes
• Neurotoxins
• Pyridinium Compounds
• Ubiquinone
• 1-methyl-4-phenyl-2,3-dihydropyridinium
• Monoamine Oxidase
• Ubiquinone Q2
• ubiquinol
• ubiquinone 9
• 1-Methyl-4-phenylpyridinium

Topics

• 1-Methyl-4-phenylpyridinium (metabolism)
• Animals
• Biotransformation
• Liposomes
• Male
• Monoamine Oxidase (metabolism)
• Neurotoxins (metabolism)
• Oxidation-Reduction
• Pyridinium Compounds (metabolism)
• Rats
• Rats, Wistar
• Synaptosomes (drug effects, metabolism)
• Ubiquinone (analogs & derivatives, metabolism)