Lee E S, Charlton C G
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Pharmacol Biochem Behav. 2001 Sep;70(1):105-14. doi: 10.1016/s0091-3057(01)00588-3.
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.
1-甲基-4-苯基吡啶鎓（MPP(+)）和S-腺苷-L-甲硫氨酸（SAM）会引发帕金森病（PD）样变化。SAM和MPP(+)需要其带电荷的S-甲基和N-甲基基团，因此PD样症状可能与其调节甲基化过程的能力有关。通过磷脂酰乙醇胺-N-甲基转移酶（PEMT），SAM依赖的磷脂酰乙醇胺（PTE）甲基化生成磷脂酰胆碱（PTC），以及PTC水解形成细胞毒性剂溶血磷脂酰胆碱（lyso-PTC），是MPP(+)作用的潜在位点。在本研究中，测定了MPP(+)对PTE甲基化生成PTC以及lyso-PTC产生的影响。结果表明，SAM增加了PTC和lyso-PTC。大鼠纹状体显示出最高的PEMT活性和lyso-PTC形成，这与纹状体是PD中受影响的主要结构这一事实相符。MPP(+)显著增强了大鼠肝脏和大脑中的PEMT活性以及lyso-PTC的形成。MPP(+)增加了PEMT对SAM的亲和力和V(max)。1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的作用较小且被司来吉兰（单胺氧化酶B抑制剂）抑制。MPP(+)的去甲基类似物无活性，但一些带电荷的MPP(+)类似物显示出与MPP(+)相当的作用。SAM和MPP(+)可增加的lyso-PTC导致大鼠运动活动严重受损。这些结果表明，SAM和MPP(+)对磷脂甲基化具有互补作用。因此，SAM诱导的高甲基化可能参与PD的病因学，磷脂甲基化增加可能是MPP(+)导致帕金森综合征的机制之一。
