Hideo Yoshizumi

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

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.

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.

Involvement of the Drug Transporters P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2 in Telithromycin Transport

ABSTRACT The present study aims to investigate the role of P glycoprotein and multidrug resistance-associated protein (Mrp2) in the transport of telithromycin, a newly developed ketolide antibiotic, in vitro and in vivo. The in vitro experiments revealed that the intracellular accumulation of telithromycin in adriamycin-resistant human chronic myelogenous leukemia cells (K562/ADR) overexpressing P glycoprotein was significantly lower than that in human chronic myelogenous leukemia cells (K562/S) not expressing P glycoprotein. Cyclosporine significantly increased the intracellular accumulation of telithromycin in K562/ADR cells. When telithromycin was coadministered intravenously with cyclosporine in Sprague-Dawley (SD) rats, cyclosporine significantly delayed the disappearance of telithromycin from plasma and decreased its systemic clearance to 60% of the corresponding control values. Hepatobiliary excretion experiments revealed that cyclosporine almost completely inhibited the biliary clearance of telithromycin, suggesting that telithromycin is a substrate of P glycoprotein and a potential substrate of Mrp2. Moreover, the biliary clearance of telithromycin was significantly decreased by 80% in Eisai hyperbilirubinemic mutant rats with a hereditary deficiency in Mrp2, indicating that Mrp2, as well as P glycoprotein, plays an important role in the biliary excretion of telithromycin. When the effect of telithromycin on the biliary excretion of doxorubicin, a substrate of P glycoprotein and Mrp2, was examined in SD rats, telithromycin significantly decreased the biliary clearance of doxorubicin by 80%. Results obtained from this study indicate that telithromycin is a substrate of both P glycoprotein and Mrp2, and these transporters are involved in the hepatobiliary transport of telithromycin.

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.

Effects of enoxacin on renal and metabolic clearance of theophylline in rats.

The effects of enoxacin and its metabolite 4-oxoenoxacin on the disposition of theophylline were investigated in rats. Systemic clearance of theophylline was significantly decreased by approximately 40, 46, and 50% after oral coadministration of 25, 100, and 200 mg of enoxacin per kg, respectively. No significant changes in the volume of distribution of theophylline were observed. 4-Oxoenoxacin had no direct effect on theophylline disposition. Significant changes in urinary excretion of theophylline and its metabolites were observed. (i) Urinary excretion of unchanged theophylline was significantly increased in proportion to increases in enoxacin dosage. (ii) Decreases in renal clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid were observed. (iii) The percent decreases in the metabolic clearance of 1-methyluric acid were dependent on enoxacin dosage. It is likely that enoxacin inhibits the elimination process, which depends on cytochrome P-450-mediated isozymes for N demethylation and oxidation, and that the capacity of the inhibitory effect of enoxacin is greater in the N-demethylation pathway than it is in oxidation.

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.

Endotoxin impairs biliary transport of sparfloxacin and its glucuronide in rats.

The effect of endotoxin on glucuronidation and hepatobiliary transport of quinolone antimicrobial agents was investigated in rats using sparfloxacin and p-nitrophenyl glucuronide as model drugs. The biliary clearance experiments were performed 24 h after a single intraperitoneal injection of endotoxin (1 mg/kg). Endotoxin significantly delayed the disappearance of sparfloxacin from plasma and increased plasma concentration of its glucuronide after intravenous injection of sparfloxacin (10 mg/kg). Significant decreases in the systemic clearance of sparfloxacin and the biliary clearance of sparfloxacin and the glucuronide were observed. Endotoxin had no effect on in vitro glucuronidation activity using p-nitrophenol as a substrate. When p-nitrophenyl glucuronide (8 mg/kg) was administered in endotoxin-pretreated rats, significant decreases in the systemic clearance, biliary clearance and renal clearance of p-nitrophenyl glucuronide were observed. These findings suggest that endotoxin decreases the biliary excretion of sparfloxacin and its glucuronide probably due to impairment of their hepatobiliary transport systems and renal handling.

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.