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Biomedical subjects

M Nakajima

Publications and source records attributed to M Nakajima.

At least 343 records · Page 19Linked to original sources
PubMed1998

Involvement of CYP1A2 in mexiletine metabolism.

AIMS: Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CYP1A2 in mexiletine metabolism. METHODS: Human CYP isoforms involved in mexiletine metabolism were investigated using microsomes from human liver and B-lymphoblastoid cells expressing human CYPs. The contributions of CYP1A2 and CYP2D6 to mexiletine metabolism were estimated by the relative activity factor (RAF). RESULTS: Mexiletine p- and 2-hydroxylase activities in human liver microsomes were inhibited by ethoxyresorufin and furafylline as well as quinidine. Mexiletine p- and 2-hydroxylase activities in microsomes from nine human livers correlated significantly with bufuralol 1'-hydroxylase activity (r = 0.907, P < 0.001 and r = 0.886, P < 0.01, respectively). Microsomes of B-lymphoblastoid cells expressing human CYP1A2 exhibited lower mexiletine p- and 2-hydroxylase activities than those expressing human CYP2D6. It was estimated by RAF that the major isoform involved in mexiletine metabolism was CYP2D6, and the contribution of CYPIA2 to both mexiletine p- and 2-hydroxylase activities was 7-30% in human liver microsomes. However, the Km values of the expressed CYP1A2 (approximately 15 microM) were almost identical with those of the expressed CYP2D6 (approximately 22 microM) and human liver microsomes. CONCLUSIONS: Mexiletine is a substrate of CYP1A2. The data obtained in this study suggest that the interaction of mexiletine with theophylline might be due to competitive inhibition of CYP1A2.

Anti-Arrhythmia Agents↗
PubMed1998

Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2.

AIMS: The aim of the study was to clarify whether the pharmacokinetic interaction between theophylline and mexiletine is mediated by inhibition of CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2. METHODS: The inhibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacetin O-deethylation, a marker reaction of CYP1A2, were studied using human liver microsomes and cDNA-expressed CYP1A2. RESULTS: Propafenone and mexiletine inhibited phenacetin O-deethylation with IC50 values of 29 and 37 microM, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC50 >1 mM). Amiodarone, bepridil, aprindine, lignocaine, flecainide and quinidine inhibited phenacetin O-deethylation in a concentration-dependent manner, although the inhibitory effects were relatively weak with IC50 values ranging from 86 to 704 microM. Propafenone and mexiletine selectively abolished the high-affinity component of phenacetin O-deethylation in human liver microsomes. In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2. CONCLUSIONS: These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.

Anti-Arrhythmia Agents↗
PubMed1998

A naturally occurring functional allele of the rice waxy locus has a GT to TT mutation at the 5' splice site of the first intron.

In cultivated rice two wild-type alleles, Wxa and Wxb, predominate at the waxy locus, which encodes granule-bound starch synthase. The activity of Wxa is 10-fold higher than that of Wxb at the level of both protein and mRNA. Wxb has a +1G to T mutation at the 5' splice site of the first intron. Sequence analysis of Wxb transcripts revealed that splicing occurs at the mutant AG/UU site and at two cryptic sites: the first is A/GUU, one base upstream of the original site and the second is AG/GU found approximately 100 bases upstream of the mutant splice site. We introduced single base mutations to the 5' splice sites of both Wxa and Wxb, fused with the gus reporter gene and introduced them into rice protoplasts. Analysis of GUS activities and transcripts indicated that a G to T mutation in Wxa reduced GUS activity and the level of spliced RNA. Conversely, a T to G mutation of Wxb restored GUS activity and the level of spliced RNA to that of wild-type Wxa. These results demonstrated that the low level expression of Wxb results from a single base mutation at the 5' splice site of the first intron. It is of interest that the Wxb allele of rice carrying the G to T mutation of intron 1 has been conserved in the history of rice cultivation because there is a low amylose content of the seed caused by this mutation.

Alleles↗
PubMed1998

Differential diagnosis of mucin-producing tumors of the pancreas by intraductal ultrasonography and peroral pancreatoscopy.

BACKGROUND AND STUDY AIMS: Although mucin producing tumors of the pancreas have been recently recognized as premalignant or malignant neoplasms, their diagnosis and management have been undetermined as yet. The aim of this study was to evaluate the capability of intraductal ultrasonography (IDUS) and peroral pancreatoscopy (PPS) in the differential diagnosis of mucin-producing tumors compared to that of other diagnostic tools. PATIENTS AND METHODS: From 1986 to 1997, 31 patients with mucin-producing tumors of the pancreas underwent surgery. RESULTS: Histologically, in patients with adenocarcinoma, papillary tumorous lesions within the pancreatic ducts were 3 mm or more in maximum height. The detection rates for such lesions were 29% with US, 21% with CT, 86% with EUS, 100% with IDUS and 83% with PPS. In patients with adenocarcinoma, PPS revealed taller papillary lesions with redness and/or capillary vessels. Biopsy and cytology during ERCP and under PPS direct vision had a sensitivity of about 60 % in the differential diagnosis between malignancy and benign diseases. CONCLUSIONS: Mucin-producing tumors of the pancreas with papillary tumorous lesions of 3 mm or more in maximum height should be considered as adenocarcinomas. The combined use of IDUS and PPS with biopsy and cytology is now considered the best for the differential diagnosis of mucin-producing tumors of the pancreas.

Adenocarcinoma, Mucinous↗
PubMed1998

EUS-guided fine aspiration biopsy (FNA)--indications and hazards.

Ultrasound endoscopes with mechanical sector forward scan transducers make it possible to perform FNA under EUS, and drainage by tracing the needle in the ultrasound pictures by using the same monitor unit as for radial scan ultrasound endoscopes for EUS diagnosis. It is important to diagnose the lesions from the histological findings; however, there remain some problems about false negatives, histological diagnosis from very tiny materials, and the risk of disseminating the malignant cells by the procedure.

Biopsy, Needle↗
PubMed1998

Diastereospecific kinetics of nicotine N'-oxidation in rat liver microsomes.

1. In kinetic studies, both Eadie-Hofstee plots for cis- and trans-nicotine-1'-N-oxide formation from nicotine in rat liver microsomes were linear. For the formation of cis- and trans-nicotine-1'-N-oxide, the apparent K(m) were 0.240 +/- 0.069 and 1.524 +/- 0.951 mM respectively. Corresponding Vmax were 1.52 +/- 0.48 and 1.19 +/- 0.74 nmol/mg/min respectively. 2. The formation of cis-nicotine-1'-N-oxide was greater than the formation of trans-nicotine-1'-N-oxide in rat liver microsomes and the intrinsic clearance of cis-nicotine-1'-N-oxide formation was 8.1-fold greater than that of trans-nicotine-1'-N-oxide formation. 3. The formation of both cis- and trans-nicotine-1'-N-oxide in rat liver microsomes was inhibited by the addition of 1-(1-naphthyl)-2-thiourea or by heat-treatment of microsomes. 2-Diethylaminoethyl-2, 2-diphenylvalerate (SKF525A) and carbon monoxide did not affect these activities even at high concentrations. 4. Formations of cis- and trans-nicotine-1'-N-oxide correlated significantly with each other (r = 0.862, p < 0.01). These results suggested that the same flavin-containing monooxygenase (FMO) isoform is responsible for the formation of cis- and trans-nicotine-1'-N-oxide in rat liver.

Animals↗
PubMed1998

Interaction mode of the phe-phenyl group of thrombin receptor-tethered ligand SFLLRNP in receptor activation.

Phenylalanine at position 2 of thrombin receptor-tethered ligand peptide (SFLLRNP) is crucially important for the activation of thrombin receptor. Its substitution by para-fluorophenylalanine [(p-F)Phe] enhanced several times the activity in human epithelial-like SH-EP cells [Nose et al. (1993) Biochem. Biophys. Res. Commun. 193, 694-699]. To clarify the interaction mode of Phe-2-phenyl in receptor activation, a series of analogs having chemical modifications on the benzene ring of Phe-2 were synthesized and examined for their ability to induce the aggregation of human platelets. When the fluorine atom was placed at the meta or ortho position, the resulting analogs exhibited considerably diminished activity (about 10-20% of para-derivative), indicating that the substitution is allowed only at the para position. The derivative with pentafluorophenylalanine was totally devoid of activity. These results suggested that Phe-2 requires hydrogen atom(s) on the benzene ring presumably for interaction with the receptor. No activity enhancement was observed for analogs with para-chloro-, bromo-, or iodophenylalanine, indicating the importance of the high electronegativity of fluorine to intensify the dipole of CH(s) remaining in the Phe-2-benzene ring. Inactivity of analogs having para-iodophenylalanine and homophenylalanine indicated the importance of the size of para substituents, and the placement of hydroxyl, nitro, and trifluoromethyl groups at the para position led to no activity. The interaction of Phe-2 of SFLLRNP appeared to be structurally restricted to a limited space in the receptor. The results suggested the presence of face-to-edge pi-pi interaction based upon the CH/pi interaction between the ligand Phe-2-phenyl group and the receptor aromatic group.

Amino Acid Sequence↗
PubMed1998

Gene cloning and expression of cytosolic glutathione reductase in rice (Oryza sativa L.).

We have isolated a cDNA (RGRC2) encoding glutathione reductase (GR) from rice (Oryza sativa L.). The comparison of deduced amino acid sequences from RGRC2 and other plant GR cDNAs indicated that RGRC2 encodes a putative cytosolic isoform. The recombinant RGRC2 protein had enzymatic properties comparable to those of GR from rice embryo. Subcellular fractionation showed that the RGRC2 protein is localized primarily in cytosol. mRNA and protein of RGRC2 were observed mainly in roots and calli but little in leaf tissues. Southern blot analysis showed that the RGRC2 gene exists as a single copy gene. Here, we have also isolated a genomic clone completely corresponding to RGRC2. The RGRC2 gene is split into 16 exons spread about 7.4 kb of chromosomal DNA, with coding sequence beginning in the 2nd exon and ending in the 16th exon. From the presence of two ABA-responsive elements in the 5'-flanking region of RGRC2, we examined the expression in rice seedlings treated with ABA and the ABA-related environmental stresses, chilling, drought and salinity. The expression of RGRC2 was strongly induced by all these treatments. We suggest that the expression of the rice cytosolic GR gene is regulated via ABA-mediated signal transduction pathway under environmental stresses.

5' Untranslated Regions↗
PubMed1998

A neurotrophic pyrimidine compound, MS-818, enhances EGF-induced restoration of gastric epithelial wounds in vitro.

MS-818 is a novel synthetic pyrimidine compound that stimulates nerve regeneration and promotes synthesis of various growth factors and differentiation of astrocytes. Effects of MS-818 on gastric epithelial cells were assessed using a wound repair model with primary cultured gastric epithelial cells from rabbits. A round wound with a constant cell-free area was created and the process of restoration was monitored by measuring wound size every 12 h. Cell proliferation was monitored by sequential staining with BrdU. As previously reported, EGF (10 ng/ml) accelerated wound repair by promoting cell migration and proliferation. Although MS-818 alone had no effects, MS-818 (10-100 microM) enhanced EGF-induced acceleration of gastric epithelial restoration, including cell migration and proliferation. Although the detailed mechanism of action of this agent is still unclear, MS-818 might have favorable effects on in vivo gastric mucosal repair.

Animals↗
PubMed1998

Evaluation of sleep using ambulatory skin potential recording: differences between morning and evening type.

In order to validate the evaluation of sleep using cassette type ambulatory skin potential measurement system (C-SPA), sleep duration variables extracted from 24 h recordings were compared between two groups (16 of the intermediate type and 16 of the evening type) with different sleep-wake habits rated by Morningness and Eveningness Questionnaires (MEQ). Compared with the intermediate type, the evening type subjects go to bed and get up later, have difficulty in falling asleep and more frequently awaken during sleep. Thus, the sleep variables by C-SPA provide valuable information about duration of sleep and differentiate the sleep-wake habits.

Activity Cycles↗
PubMed1998

Immunohistochemical and ultrastructural studies of basal cells, Clara cells and bronchiolar cuboidal cells in normal human airways.

Immunohistochemical studies were made of the distribution of various cytokeratins (CK), Clara cell secretory protein (CC10), surfactant protein A (SP-A) and type VII collagen in normal human airways. Electron microscopic studies were made to identify hemidesmosomes and anchoring fibrils on the basal surfaces of the epithelial cells. CK19 was detected in all epithelial cells, and CK17 in all basal cells. CK14 was coexpressed in a few basal cells, and this coexpression was decreased in the distal airways. Two types of basal cells were recognized. One type, found mainly in large airways, was characterized by abundant intermediate filaments and well-developed hemidesmosomes and anchoring fibrils. The second type contained few intermediate filaments and poorly developed hemidesmosomes and anchoring fibrils. Reactivity for type VII collagen was found along the basement membrane throughout the airways, but not in the alveoli. Clara cells were reactive for CC10 and CK17, but not for CK14 and SP-A. The bronchiolar cuboidal cells in the respiratory bronchioles were positive only for CK19. Surfactant protein A was present only in type II alveolar epithelial cells. Thus, two types of basal cells are present in airways, and the bronchiolar cuboidal cells appear distinct from these basal cells, Clara cells and type II alveolar epithelial cells.

Adult↗
PubMed1998

Arbutin increases the pigmentation of cultured human melanocytes through mechanisms other than the induction of tyrosinase activity.

We assessed the effects of arbutin on the pigmentation of cultured normal human melanocytes. As indicated by a cell-blotting assay, arbutin at concentrations in the range of 0.5-8 mM increased the pigmentation of the cultured melanocytes, while kojic acid at concentrations in the range of 0.5-4 mM decreased the pigmentation. The pigmentation-augmenting effect of arbutin was further confirmed by the results of a cell-pelleting assay, the traditional method of assessment. Treatment of the cells with arbutin increased the melanin content of the cells and the protein content as well. On the other hand, the tyrosinase activity in the cells was reduced by arbutin treatment. The levels of transcription of tyrosinase and tyrosinase related protein-1 genes were not affected by arbutin treatment as indicated by a semi-quantitative reverse transcription-polymerase chain reaction assay. These results demonstrate that arbutin promotes an increase in pigmentation of cultured human melanocytes that is not mediated by augmented tyrosinase activity.

Arbutin↗
PubMed1998

[Investigation of the influence of hemodialysis membranes and factors associated with hemodialysis on serum (1-->3)-beta-D-glucan].

The measurement of serum (1-->3)-beta-D-glucan (beta-glucan) is commonly used in the clinical stage. Although it has been considered very useful in the early diagnosis of deep mycosis, it is influenced by several factors, one of which is hemodialysis. Therefore, we decided to investigate clinically the influence of hemodialysis membranes on serum beta-glucan. Plasma samples were collected from 26 patients receiving hemodialysis in Kawasaki Medical School Hospital. The kinds of hemodialysis membranes examined were four synthetic polymers and three natural polymers. We also measured beta-glucan in five washing liquids used in the hemodialysis circuit, five dialyzates, two sodium heparin and two filling liquids for wet type dialyzers to investigate the influence of other factors associated with hemodialysis on serum beta-glucan. Elevations of beta-glucan were observed in some cases treated by hemodialysis apparatus using a saponified cellulose acetate membrane. But, in all cases treated by hemodialysis using a cellulose triacetate membrane, slight elevations of beta-glucan were observed. No significant increases in beta-glucan after hemodialysis were observed in the cases treated by hemodialysis using a synthetic polymer membrane. Elevations of beta-glucan is sodium heparin and in one of the filling liquids for the wet type dialyzer were observed. We, therefore, concluded that there are some other factors having an effect on serum beta-glucan besides the hemodialysis membrane in the patients treated by hemodialysis.

Adolescent↗
PubMed1998

Serum KL-6 level as a monitoring marker in a patient with pulmonary alveolar proteinosis.

A raised serum level of KL-6 is known to exist in active pulmonary fibrosis and KL-6 may be produced and secreted by type II pneumocytes. A case is described of pulmonary alveolar proteinosis with high serum KL-6 levels. The serum KL-6 level decreased after whole lung washing and correlated with symptoms, opacities on the chest radiograph, and arterial blood gas measurements. The serum KL-6 level may represent a useful marker for pulmonary alveolar proteinosis.

Adult↗
PubMed1998

Detection of activated platelets in urine by double immunofluorescence in children with IgA nephropathy.

The relationship between the activation of platelets (PLT) in urine and renal histological findings in children with IgA nephropathy (IgAN), thin basement membrane disease (TBMD), and minimal-change nephrotic syndrome (MCNS) was examined. The ratio of activated PLT to total PLT (activated and nonactivated PLT) was examined by double immunofluorescence using rhodamine-conjugated P selectin antibody (activated PLT) and fluorescein isothiocyanate conjugated PLT membrane glycoprotein antibody (GPIIb/IIIa, total PLT); the effect of urine on activation on PLT was also investigated. The number of activated PLT and the ratio of activated PLT to total PLT in urinary sediments were significantly higher in children with IgAN with diffuse mesangial proliferation than in those with TBMD or MCNS. PLT were activated by addition of urine in 13 out of 27 children with IgAN, and the activity was higher in the urine of those with active glomerular or interstitial lesions, while the urine of children with TBMD or MCNS had no effect. The presence of activated PLT and the effect of urine on PLT activation may be associated with the active glomerular or interstitial lesions in IgAN.

Adolescent↗
PubMed1998

D-penicillamine treatment for chronic sensory ataxic neuropathy associated with Sjögren's syndrome.

Beneficial treatment has not been established for chronic sensory ataxic neuropathy associated with Sjögren's syndrome (CSAN-SS). We describe two patients with CSAN-SS who clinically improved in response to D-penicillamine treatment. Their neuropathic symptoms were lessened after D-penicillamine, and the results of electrophysiologic studies support the clinical improvement. D-Penicillamine can be considered a potentially beneficial agent in the treatment of CSAN-SS.

Adult↗