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

被引:39
作者
Aoyama, K
Matsubara, K [1 ]
Okada, K
Fukushima, S
Shimizu, K
Yamaguchi, S
Uezono, T
Satomi, M
Hayase, N
Ohta, S
Shiono, H
Kobayashi, S
机构
[1] Asahikawa Med Coll, Dept Hosp Pharm & Pharmacol, Asahikawa, Hokkaido 0788510, Japan
[2] Asahikawa Med Coll, Dept Legal Med, Asahikawa, Hokkaido 0788510, Japan
[3] Shimane Med Univ, Inst Cent Lab, Izumo, Shimane 693, Japan
[4] Shimane Med Univ, Dept Internal Med 3, Izumo, Shimane 693, Japan
[5] Hiroshima Univ, Inst Pharmaceut Sci, Hiroshima, Japan
关键词
Parkinson's disease; N-methylation; nicotinamide; aging;
D O I
10.1007/s007020070047
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 100mg to 26 parkinsonians and 20 controls consisted of 16 other neurogenic disease patients and 4 healthy volunteers. The urine was collected for 4h, 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 N-1-methylnicotinamide decreased along with aging both in PD patients and controls. In younger (65 years old or younger) PD patients, the excretion amount of N-1-methylnicotinamide was significantly higher than that in younger controls. The decline rate of N-1-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 (N-1-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.
引用
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页码:985 / 995
页数:11
相关论文
共 34 条
[11]  
KOTAKE Y, 1995, J NEUROCHEM, V65, P2633
[12]   A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in parkinsonian cerebrospinal fluid [J].
Maruyama, W ;
Abe, T ;
Tohgi, H ;
Dostert, P ;
Naoi, M .
ANNALS OF NEUROLOGY, 1996, 40 (01) :119-122
[13]   beta-Carbolinium cations, endogenous MPP(+) analogs, in the lumbar cerebrospinal fluid of patients with Parkinson's disease [J].
Matsubara, K ;
Kobayashi, S ;
Kobayashi, Y ;
Yamashita, K ;
Koide, H ;
Hatta, M ;
Iwamoto, K ;
Tanaka, O ;
Kimura, K .
NEUROLOGY, 1995, 45 (12) :2240-2245
[14]   NOVEL S-ADENOSYLMETHIONINE-DEPENDENT INDOLE-N-METHYLATION OF BETA-CARBOLINES IN BRAIN PARTICULATE FRACTIONS [J].
MATSUBARA, K ;
NEAFSEY, EJ ;
COLLINS, MA .
JOURNAL OF NEUROCHEMISTRY, 1992, 59 (02) :511-518
[15]  
MORANO A, 1994, ACTA NEUROL SCAND, V89, P164
[16]   Isoquinoline neurotoxins in the brain and Parkinson's disease [J].
Nagatsu, T .
NEUROSCIENCE RESEARCH, 1997, 29 (02) :99-111
[17]   AN ENDOGENOUS SUBSTANCE OF THE BRAIN, TETRAHYDROISOQUINOLINE, PRODUCES PARKINSONISM IN PRIMATES WITH DECREASED DOPAMINE, TYROSINE-HYDROXYLASE AND BIOPTERIN IN THE NIGROSTRIATAL REGIONS [J].
NAGATSU, T ;
YOSHIDA, M .
NEUROSCIENCE LETTERS, 1988, 87 (1-2) :178-182
[18]   (R)Salsolinol N-methyltransferase activity increases in parkinsonian lymphocytes [J].
Naoi, M ;
Maruyama, W ;
Nakao, N ;
Ibi, T ;
Sahashi, K ;
Benedetti, MS .
ANNALS OF NEUROLOGY, 1998, 43 (02) :212-216
[19]   A N-METHYLTRANSFERASE IN HUMAN-BRAIN CATALYZES N-METHYLATION OF 1,2,3,4-TETRAHYDROISOQUINOLINE INTO N-METHYL-1,2,3,4-TETRAHYDROISOQUINOLINE, A PRECURSOR OF A DOPAMINERGIC NEUROTOXIN, N-METHYLISOQUINOLINIUM ION [J].
NAOI, M ;
MATSUURA, S ;
TAKAHASHI, T ;
NAGATSU, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 161 (03) :1213-1219
[20]  
NAOI M, 1993, ADV NEUROL, V60, P212