Akira Tatematsu

Presence of 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, novel endogenous amines, in parkinsonian and normal human brains

2-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were identified for the first time as novel endogenous amines in parkinsonian and normal human brains by gas chromatography-mass spectrometry. It is of interest that these tetrahydroisoquinolines are analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which produces Parkinsons disease.

Presence of tetrahydroisoquinoline, a parkinsonism-related compound, in foods

We detected 1,2,3,4-tetrahydroisoquinoline (TIQ) in the various foods studied. Makino et al. reported that TIQ was detected in cheese, wine and cocoa. We confirmed their findings, except for the presence of TIQ in cocoa, which could not be detected because of impurities in the extract

Accumulation of furancarboxylic acids in uremic serum as inhibitors of drug binding

3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, 3-carboxy-4-methyl-5-pentyl-2-furanpropionic acid, 3-carboxy-4-methyl-5-ethyl-2-furanpropionic acid and 3-carboxy-5-propyl-2-furanpropionic acid were detected in uremic serum using gas chromatography-mass spectrometry. Mass chromatography revealed that the serum concentrations of the furancarboxylic acids especially 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, were increased in the chronic hemodialysis patients and that the acids could not be removed by conventional hemodialysis due to their strong binding to plasma protein. 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid was also quantitated in uremic serum by high-performance liquid chromatography. Serum level of the acid in uremic patients showed significant but weak correlation with serum level of urea and duration on hemodialysis. Equilibrium dialysis demonstrated that 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid and 3-carboxy-4-methyl-5-pentyl-2-furanpropionic acid inhibited the bindingof salicylate and 5,5-diphenylhydantoin to albumin. In conclusion, the furancarboxylic acids especially 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid were accumulated in uremic serum as inhibitors of drug binding.

Elevated Serum Levels of 3-Deoxyglucosone, a Potent Protein-Cross-Linking Intermediate of the Maillard Reaction, in Uremic Patients

3-Deoxyglucosone (3-DG) has been identified as an intermediate of the Maillard reaction in vitro. We measured serum 3-DG levels using gas chromatography/mass spectrometry and found a marked elevation in serum 3-DG levels in uremic patients compared with healthy subjects. The uremic patients with diabetes showed significantly higher serum concentrations of 3-DG than those without diabetes. 3-DG was demonstrated to be a potent protein-cross-linking agent in the reaction with lysozyme, leading to browning, fluorescence formation and polymerization of the protein by formation of advanced glycation end products (AGE). The increase in serum 3-DG levels in the uremic patients suggests that 3-DG may be responsible for the development of uremic complications by promoting the formation of AGE.

Migration of tetrahydroisoquinoline, a possible parkinsonian neurotoxin, into monkey brain from blood as proved by gas chromatography-mass spectrometry.

1,2,3,4-Tetrahydroisoquinoline (TIQ) was quantitated by use of gas chromatography-mass spectrometry in brains and livers of marmosets which showed parkinsonism after daily subcutaneous injection of TIQ. TIQ showed greatly increased levels in the brains and livers of the TIQ-treated marmosets, with no detectable metabolites of TIQ. TIQ was present as an endogenous amine in the brains and livers of saline-treated marmosets at very low concentrations. It thus seems that TIQ can pass easily through the blood-brain barrier but cannot be metabolized in the brain or the liver. It is possible that TIQ accumulated in the brain may produce parkinsonism.

Endogenous synthesis of N-methylsalsolinol, an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, in rat brain during in vivo microdialysis with salsolinol, as demonstrated by gas chromatography—mass spectrometry

N-Methylsalsolinol, an analogue of 1,2,3,6-tetrahydropyridine, is present in the brains of patients with Parkinsons disease. To determine the metabolic pathway for the synthesis of N-Methylsalsolinol in the brain, salsolinol was perfused through the striatum or the substantia nigra of the rat brain by in vivo microdialysis. N-Methylsalsolinol was detected in the brain dialysate samples during microdialysis with salsolinol using gas chromatography-mass spectrometry with selected-ion monitoring. These results demonstrate that endogenous N-methylation of salsolinol into N-methylsalsolinol occurs in the brain in vivo.

Dihydropyrimidinuria: the first case in Japan.

Dihydropyrimidinuria (McKusick 222748) is a recently described disorder of pyrimidine metabolism that presents neurological symptoms different in degree. Only two cases have been reported to date (Duran et al, 1991; Henderson et al, 1993). The patients with dihydropyrimidinuria excrete large amount of dihydrouracil and dihydrothymine, and moderate amount of uracil and thymine in urine. Therefore this disease is thought to be caused by a deficiency of dihydropyrimidine amidohydrolase (DHPase; EC 3.5.2.2), the second step of pyrimidine base catabolism. The first case, reported by Duran et al (1991), was hospitalized for convulsion and disturbed consciousness at the age of 8 weeks, but whose subsequent development had been normal. The second case reported by Henderson et al (1993) presented severe developmental delay. These two patients were discovered by the urinary gas chromatography mass spectrometry (GC-MS) analysis for the neurological sick children. We report here another case of dihydropyrimidinuria which is the first case in Japan and probably the third worldwide. We discovered her by using high-performance liquid chromatography (HPLC) at the mass screening program.

Endogenous synthesis of N-methylnorsalsolinol in rat brain during in vivo microdialysis with epinine

The in vivo metabolic pathway for the synthesis of N-methylnorsalsolinol, an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was studied in the rat brain. N-Methyldopamine (epinine) was perfused at the striatum of the rat brain by in vivo microdialysis. N-Methylnorsalsolinol (NMNSAL) was identified in the brain dialysate after epinine perfusion using gas chromatography-selected-ion monitoring mass spectrometry (GC-SIM-MS). We demonstrated that NMNSAL could be synthesized from epinine with an aldehyde by the Piclet-Spengler condensation reaction in the rat brain.

Presence of N-methyldopamine in parkinsonian and normal human brains

N-Methyldopamine (epinine) has been identified for the first time in parkinsonian and normal human brains by gas chromatography-mass spectrometry. N-Methylsalsolinol and N-methylnorsalsolinol, which are analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces parkinsonism in humans, may be synthesized from N-methyldopamine by the Pictet-Spengler condensation reaction as an alternative metabolic pathway.

Mass spectrometric identification of a phorbol diester, 12-O-hexadecanoylphorbol-13-acetate, an Epstein-Barr virus-activating substance, in the soil collected from under Sapium sebiferum

Soil-extracts collected from the ground from under several Euphorbiaceae plants have been known to possess Epstein-Barr virus (EBV)-activating substances which are thought to be one of the environmental co-factors causing nasopharyngeal carcinoma (NPC) in southern part of China and Burkitts lymphoma (BL) in tropical Africa. Then, a model experiment aimed at chemical characterization of such active substances was carried out using a soil-extract around Sapium sebiferum, a Japanese representative Euphorbiaceae plant. Chromatographic separation guided by the EBV early antigen (EA) inducing activity gave a highly active fraction. Application of this fraction to desorption chemical ionization mass spectrometry identified a major active substance to be 12-O-hexadecanoylphorbol-13-acetate (HPA), which originally occurs in this plant. The method in this model experiment is suggested to be applicable to other samples from the endemic areas of NPC and BL.