Naohito Takeda

Presence of tetrahydroisoquinoline and 2-methyl-tetrahydroquinoline in Parkinsonian and normal human brains

1,2,3,4-Tetrahydroisoquinoline (TIQ) and 2-methyl-1,2,3,4-tetrahydroquinoline (2-Me-TQ) were identified for the first time by gas chromatography-mass spectrometry in the parkinsonian and normal human brains. TIQ, an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was markedly increased in the parkinsonian brain and could be an endogenous neurotoxin to induce Parkinsons disease.

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.

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.

Detection and characterization of modified nucleosides in serum and urine of uremic patients using capillary liquid chromatography–frit-fast atom bombardment mass spectrometry

To determine RNA metabolism in uremia, capillary liquid chromatography-frit-fast atom bombardment mass spectrometry was employed for the characterization of ribonucleosides in serum and urine of uremic patients, and the profiles were compared with those of healthy subjects. We have characterized 20 nucleosides in serum and 23 nucleosides in urine from both healthy subjects and uremic patients; most of them were modified nucleosides derived from tRNA breakdown products. Four metabolites derived from allopurinol were detected as exogenous nucleosides in patients receiving allopurinol; these include allopurinol-1-riboside, oxipurinol-1-riboside, oxipurinol-7-riboside and a unknown oxipurinol riboside. The endogenous and exogenous ribonucleosides were retained at higher levels in uremic serum, and may play a contributory role as toxins responsible for clinical symptoms of uremia.

PHOTOCYTOTOXICITY OF WATER‐SOLUBLE METALLOPORPHYRIN DERIVATIVES

Abstract— A new water‐soluble porphyrin derivative, 2,4‐bis(1‐decyloxyethyl)‐deuteroporphyrinyl–6,7‐bisaspartic acid(C–10‐DP), and its metal complexes (Ga, In, Sn, Zn, Mn, Cu, Ni and Fe) were examined for their physicochemical properties (absorption, fluorescene, triplet lifetime and partition coefficient) and photocytotoxicity on HeLa cells. The five derivatives with longer(>1ms) triplet lifetimes (free base, Zn, Ga, In and Sn complexes) exhibited remarkable photocytotoxicity, and the other derivatives (Mn, Cu, Ni and Fe), which had or were deduced to have fairly short (<0.01 ms) triplet lifetimes, manifested no photocytotoxicity, indicating that the triplet lifetime of these derivatives played a significant role in their photocytotoxicity. Cellular fluorescence due to C10‐DP and its gallium complex was observed mainly on the plasma membrane at the concentrations showing significant photocytotoxicity with low (<32.6%) cytotoxicity in the dark(2–10 μM).

The Selective Formose Reaction in Dimethylformamide in the Presence of Vitamin B1

Abstract The formose which was obtained from formaldehyde in the presence of base was a mixture of sugars and sugar alcohols containing over 30 components. The formose reaction has drawn much attention for 122 years from several standpoints; the chemical synthesis of edible carbohydrates from C1 compounds, an important process in the recycling of carbon sources during sustained space flights, and as a model for the prebiotic synthesis of monosaccharides. Nevertheless, because of the complexity of this product mixture (Fig. 1b), the formose reaction has not been completely elucidated and the product (so called formose) has not been useful yet. During the long formose history few products were isolated from the formose mixture and identified, except in work from our laboratories.