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 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.
Aoyama
K
K
Department of Hospital Pharmacy & Pharmacology, Asahikawa Medical College, Japan.
Matsubara
K
K
Okada
K
K
Fukushima
S
S
Shimizu
K
K
Yamaguchi
S
S
Uezono
T
T
Satomi
M
M
Hayase
N
N
Ohta
S
S
Shiono
H
H
Kobayashi
S
S
D000368:Aged; D000375:Aging / Q000378:metabolism; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D002243:Carbolines / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism*; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009536:Niacinamide / Q000032:analysis / Q000493:pharmacokinetics* / Q000652:urine; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism*
D002243:Carbolines; D007546:Isoquinolines; D009536:Niacinamide; D003577:Cytochrome P-450 Enzyme System; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase