1-Methyl-4-phenyl-pyridinium increases S-adenosyl-L-methionine dependent phospholipid methylation.
1-Methyl-4-phenyl-pyridinium (MPP(+)) and S-adenosyl-L-methionine (SAM) cause Parkinson's disease (PD)-like changes. SAM and MPP(+) require their charged S-methyl and N-methyl groups, so the PD-like symptoms may be related to their ability to modulate the methylation process. The SAM-dependent methylation of phosphatidylethanolamine (PTE) to produce phosphatidylcholine (PTC), via phosphatidylethanolamine-N-methyltransferase (PEMT), and the hydrolysis of PTC to form lyso-PTC, a cytotoxic agent, are potential loci for the action of MPP(+). In this study, the effects of MPP(+) on the methylation of PTE to PTC and the production of lyso-PTC were determined. The results showed that SAM increased PTC and lyso-PTC. The rat striatum showed the highest PEMT activity and lyso-PTC formation, which substantiate with the fact that the striatum is the major structure that is affected in PD. MPP(+) significantly enhanced PEMT activity and the formation of lyso-PTC in the rat liver and brain. MPP(+) increased the affinity and the V(max) of PEMT for SAM. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) effect was lesser and inhibited by deprenyl (MAO-B inhibitor). The nor-methyl analogs of MPP(+) were inactive, but some of the charged analogs of MPP(+) showed comparable effects to those of MPP(+). Lyso-PTC that can be increased by SAM and MPP(+) caused severe impairments of locomotor activities in rats. These results indicate that SAM and MPP(+) have complementary effects on phospholipid methylation. Thus, SAM-induced hypermethylation could be involved in the etiology of PD and an increase of phospholipid methylation could be one of the mechanisms by which MPP(+) causes parkinsonism.
Lee
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College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Charlton
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D015655:1-Methyl-4-phenylpyridinium / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006540:Herbicides; D010743:Phospholipids; D008780:Methyltransferases; C434266:S-adenosyl-L-methionine-dependent N-methyltransferase; D015655:1-Methyl-4-phenylpyridinium