Aoyama K, Matsubara K, Okada K, Fukushima S, Shimizu K, Yamaguchi S, Uezono T, Satomi M, Hayase N, Ohta S, Shiono H, Kobayashi S
Department of Hospital Pharmacy & Pharmacology, Asahikawa Medical College, Japan.
J Neural Transm (Vienna). 2000;107(8-9):985-95. doi: 10.1007/s007020070047.
The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is may be initiated or precipitated by endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. The higher cerebrospinal fluid levels of N-methylated azaheterocyclic amines, such as beta-carboline and tetrahydroisoquinoline, have been found in parkinsonian patients compared with age-matched controls. To estimate the N-methylation ability for azaheterocyclic amines in parkinsonian patient, nicotinamide was dosed with 100 mg to 26 parkinsonians and 20 controls consisted of 16 other neurogenic disease patients and 4 healthy volunteers. The urine was collected for 4 h, and then analyzed urinary its metabolites by an improved HPLC method. Nicotinamide has a pyridine ring in its structure and may be metabolized through the pathways similar to those for the endogenous neurotoxins. The urinary excretions of nicotinamide metabolites were significantly affected by aging. The excretion of N1-methylnicotinamide decreased along with aging both in PD patients and controls. In younger (65 years old or younger) PD patients, the excretion amount of N1-methylnicotinamide was significantly higher than that in younger controls. The decline rate of N1-methylnicotinamide excretion in parkinsonians was significantly greater than that in controls; the rate is more than 2-fold higher in parkinsonian patients. The age-associated decrease in 1-methyl-2-pyridone-5-carboxyamide excretion was observed only in parkinsonian patients, but not in controls. The total excreted amount of N-methylated metabolites (N1-methylnicotinamide plus 1-methyl-2-pyridone-5-carboxyamide) was also observed the age-related decline in both groups. The urinary excretions of nicotinamide and nicotinamide-N-oxide were not influenced by aging. These results would indicate that the excess N-methylation ability for azaheterocyclic amines before the onset had been implicated in PD. On the other hand, the present results suggested that the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的发现引发了一种假说，即帕金森病（PD）可能是由内源性毒素在遗传易感性个体中通过与MPTP类似的机制引发或促成的。与年龄匹配的对照组相比，帕金森病患者脑脊液中N-甲基化氮杂环胺（如β-咔啉和四氢异喹啉）的水平更高。为了评估帕金森病患者中氮杂环胺的N-甲基化能力，给26名帕金森病患者和20名对照组（包括16名其他神经源性疾病患者和4名健康志愿者）服用了100mg烟酰胺。收集尿液4小时，然后用改进的高效液相色谱法分析尿液中的代谢产物。烟酰胺在其结构中有一个吡啶环，可能通过与内源性神经毒素相似的途径进行代谢。烟酰胺代谢产物的尿排泄量受年龄影响显著。在帕金森病患者和对照组中，N1-甲基烟酰胺的排泄量均随年龄增长而下降。在较年轻（65岁及以下）的帕金森病患者中，N1-甲基烟酰胺的排泄量显著高于较年轻的对照组。帕金森病患者中N1-甲基烟酰胺排泄量的下降率显著高于对照组；帕金森病患者的下降率高出2倍以上。仅在帕金森病患者中观察到1-甲基-2-吡啶酮-5-羧酰胺排泄量随年龄相关的下降，而在对照组中未观察到。两组中N-甲基化代谢产物（N1-甲基烟酰胺加1-甲基-2-吡啶酮-5-羧酰胺）的总排泄量也观察到与年龄相关的下降。烟酰胺和烟酰胺-N-氧化物的尿排泄量不受年龄影响。这些结果表明，发病前氮杂环胺的过量N-甲基化能力与帕金森病有关。另一方面，目前的结果表明，作用于吡啶环的异常细胞色素P450或醛氧化酶活性（可作为内源性神经毒素的解毒途径）在帕金森病的病因学中作用较小。
