N-methylation ability for azaheterocyclic amines is higher in Parkinson's disease: nicotinamide loading test

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 prec ipitated by endogenous toxins by the mechanism similar to that of MPTP in g enetically-predisposed individuals. The higher cerebrospinal fluid levels o f N-methylated azaheterocyclic amines, such as beta-carboline and tetrahydr oisoquinoline, have been found in parkinsonian patients compared with age-m atched controls. To estimate the N-methylation ability for azaheterocyclic amines in parkinsonian patient, nicotinamide was dosed with 100mg to 26 par kinsonians and 20 controls consisted of 16 other neurogenic disease patient s and 4 healthy volunteers. The urine was collected for 4h, and then analyz ed urinary its metabolites by an improved HPLC method. Nicotinamide has a p yridine ring in its structure and may be metabolized through the pathways s imilar to those for the endogenous neurotoxins. The urinary excretions of n icotinamide metabolites were significantly affected by aging. The excretion of N-1-methylnicotinamide decreased along with aging both in PD patients a nd controls. In younger (65 years old or younger) PD patients, the excretio n amount of N-1-methylnicotinamide was significantly higher than that in yo unger controls. The decline rate of N-1-methylnicotinamide excretion in par kinsonians was significantly greater than that in controls; the rate is mor e than 2-fold higher in parkinsonian patients. The age-associated decrease in 1-methyl-2-pyridone-5-carboxyamide excretion was observed only in parkin sonian patients, but not in controls. The total excreted amount of N-methyl ated metabolites (N-1-methylnicotinamide plus 1-methyl-2-pyridone-5-carboxy amide) was also observed the age-related decline in both groups. The urinar y excretions of nicotinamide and nicotinamide-N-oxide were not influenced b y 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 aber rant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ri ng, that could act as detoxification routes of endogenous neurotoxins, woul d be small in the etiology of PD.