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Biomedical subjects

I Tomita

Publications and source records attributed to I Tomita.

At least 19 recordsLinked to original sources
PubMed1992

Reduced functions of intracellular Ca2+ in aggregation, secretion and protein phosphorylation of permeabilized platelets from stroke-prone spontaneously hypertensive rats.

Aggregation, secretion and 47kDa protein (P47) phosphorylation by various agonists such as thrombin, ADP and ionophore A23187 were markedly reduced in platelets from stroke-prone spontaneously hypertensive rats (SHRSP) compared with those of age-matched Wistar Kyoto rat (WKY) platelets, suggesting defective functions of intracellular Ca2+ in SHRSP platelets (Tomita et al. Hypertension 1989; 14: 304-315). To clarify the mechanism of the platelet hypofunctions, saponin permeabilized platelets were prepared to compare the responses of platelets from both rats in varying concentrations of extracellular Ca2+. The leakage of lactate dehydrogenase from saponin (15 micrograms/ml)-treated platelets was approx. 5% of total activity; the degree of the leakage in both platelets did not differ. In saponin-treated platelets, extracellular Ca2+ alone did not induce either aggregation or secretion in both strains. However, in the presence of 1-oleoyl-2-acetylglycerol (10 micrograms/ml), Ca2+ dose dependently stimulated both aggregation and secretion. Under this condition, Ca2+ sensitivity of aggregation, secretion and P47 phosphorylation in SHRSP platelets were significantly reduced compared with those in WKY platelets. These results strongly suggest that intracellular Ca2+ functions are impaired in SHRSP platelets.

Animals↗
PubMed1992

Enhancing effects of heterocyclic amines and beta-carbolines on the induction of chromosome aberrations in cultured mammalian cells.

The effects of post-treatment with heterocyclic amines and beta-carbolines on the induction of chromosome aberrations were studied in Chinese hamster CHO K-1 cells and SV40-transformed excision repair-deficient human XP2OSSV cells. The number of chromosome aberrations induced by UV and MMC were increased by post-treatment with Trp-P-1 and Trp-P-2, in both the presence and the absence of S9 mix. A alpha C, MeA alpha C, Glu-P-1, Glu-P-2, IQ, MeIQ, harman and harmine increased chromosome aberrations only in the presence of S9 mix. Glu-P-2, IQ, MeIQ, harman, and harmine did not induce chromosome aberrations by themselves at the concentrations used in this study. Trp-P-1, Trp-P-2, A alpha C, MeA alpha C and Glu-P-1 were weak clastogens by themselves, but at much higher concentrations than those at which they increased the induction of chromosome aberrations in cells pretreated with UV or MMC. Therefore, the increases in chromosome aberrations were not considered to be additive.

Amines↗
PubMed1992

Bio-antimutagenic activities of vitamin B6 in E. coli and mouse peripheral blood cells.

Pyridoxal (PL) and pyridoxal 5'-phosphate (PLP) showed a marked bio-antimutagenic effect on UV-induced mutagenesis in E. coli B/r WP2, but not in the DNA excision repair-deficient strain WP2suvrA under the condition where no cellular toxicity was observed. No delay in the first cell division was seen on post-treatment with PL after UV irradiation. PL reduced not only UV- but 4-nitroquinoline-1-oxide-induced mutation, while it was ineffective in N-methyl-N'-nitro-N-nitrosoguanidine- or gamma-ray-treated cells. These results suggest that PL promotes DNA excision repair directly or indirectly and the decrease in the amount of unrepaired DNA damage might cause the reduction of UV-induced mutations in E. coli B/r WP2. In addition to the above observation, PLP reduced the frequency of mitomycin C- (2 mg/kg, i.p.) induced micronuclei in mouse peripheral blood cells. Simultaneous or subsequent oral administration of PLP (25 mg/kg) decreased the frequency of micronucleated peripheral reticulocytes.

Animals↗
PubMed1992

Enhancing effect of heterocyclic amines and beta-carbolines on UV or chemically induced mutagenesis in E. coli.

Most heterocyclic amines and beta-carbolines--harman, norharman, harmine, harmaline--enhanced UVC (254 nm) induced mutagenesis without microsomal activation in E. coli B/r WP2. 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) was most effective and increased UVAB (295-400 nm) induced mutations as well as UVC induced ones. Trp-P-1 enhanced the frequencies of mutations induced by not only UV but also 4-nitroquinoline-1-oxide (4NQO) or 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF2), while it showed little effect on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or gamma-ray induced mutagenesis. Trp-P-1 decreased the survival of UVC irradiated cells of CM571recA. However, these effects of Trp-P-1 on UVC induced mutagenesis and lethality were not observed in WP2suvrA which is excision repair deficient. The alkaline sucrose gradient sedimentation analysis demonstrated that Trp-P-1 blocked the incision step in DNA excision repair. Further, pretreatment with Trp-P-1 before UVC irradiation showed no effect on UVC induced mutagenesis. Similar effects were also seen in the case of harman or norharman. These results suggest that heterocyclic amines and beta-carbolines inhibit DNA excision repair directly or indirectly, thus enhancing UV or chemically induced mutagenesis.

Amines↗
PubMed1992

Effects on cultured neonatal mouse calvaria of 1 alpha,25-dihydroxyvitamin D3, 26,26,26,27,27,27-hexafluoro-1 alpha,25-dihydroxyvitamin D3 and 26,26,26,27,27,27-hexafluoro-1 alpha,23S,25-trihydroxyvitamin D3.

The potency of 26,26,26,27,27,27-hexafluoro-1 alpha,25-dihydroxyvitamin D3 (26,27-F6-1,25(OH)2D3) to enhance bone calcium (Ca) mobilization in vitro was higher than that of 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). In a 48-h organ culture system using fetal rat limb bones, effects of 26,27-F6-1,25(OH)2D3 on bone resorption were similar to those of 1,25(OH)2D3. Thus, we attempted to clarify whether or not the potency of 26,27-F6-1,25(OH)2D3 in bone resorption in vitro would be higher than that of 1,25(OH)2D3. Calvarial bones from neonatal mice were used as explants and the culture period was extended to 144 from 48 h. In cultures of 0 to 48 h, both drugs increased the release of prelabeled 45Ca from cultured calvariae, in a dose-dependent manner. In cultures of 48 to 144 h, 26,27-F6-1,25(OH)2D3 was much more effective than 1,25(OH)2D3 regarding indices of bone resorption. 26,26,26,27,27,27-F6-1 alpha,23S,25-trihydroxyvitamin D3 (26,27-F6-1,23,25(OH)3D3), a main metabolite of 26,27-F6-1,25(OH)2D3 in rats, stimulated 45Ca release equipotently to 1,25(OH)2D3. In mouse bone marrow cells cultured for 7 days, the potency of 26,27-F6-1,25(OH)2D3 on osteoclast formation was much higher than 1,25(OH)2D3. These results suggest that the higher potency of 26,27-F6-1,25(OH)2D3 in bone resorption may be due at least in part to both the higher potency of 26,27-F6-1,25(OH)2D3 in osteoclast formation and the larger retention of 26,27-F6-1,23,25(OH)3D3 in calvariae.

Acid Phosphatase↗
PubMed1992

Interaction of the tumor inhibitor IKP-104, a 4(1H)-pyridinone derivative, with microtubule proteins.

The effects of a mitotic arrestant, IKP-104, which has an antitumor activity, on the in vitro polymerization and depolymerization of rat brain microtubules were investigated. IKP-104 inhibited microtubule polymerization at concentrations greater than 0.71 x 10(-6) M, and its IC50 value was determined to be 1.31 x 10(-6) M by probit analysis. Fifty-two percent of pre-polymerized microtubules depolymerized at 1.31 x 10(-6) M IKP-104. Electron micrographs of microtubules taken immediately after treatment with 1 x 10(-3) M IKP-104 revealed a fraying of microtubule ends into elongated coil-like filaments, which were composed of 2 or 3 protofilaments. When microtubule protein treated with 1 x 10(-3) M IKP-104 was cleaved by trypsin, fragments of 41, 36, 34, 23, 21, 19 and 16 kilodaltons (kDa) derived from alpha-tubulin were produced. In particular, the 19, 23, and 34 kDa fragments were characteristically observed in the trypsin cleavage of microtubules tested with IKP-104, and these fragments were not observed with untreated microtubules. The effects of IKP-104 on microtubule protein mentioned above were mostly similar to those of vinblastine (VLB) and we suggest that IKP-104 bound to the site or sites near "VLB-binding site or sites" of alpha-tubulin subunit, resulting in induction of conformational changes.

Animals↗
PubMed1992

Phospholipid metabolism in platelets from stroke-prone spontaneously hypertensive rats and Wistar Kyoto rats.

Platelets from stroke-prone spontaneously hypertensive rats (SHRSP) show severe hypofunctions accompanied by defective protein (P47) phosphorylation. To examine the mechanism of platelet hypofunctions, phospholipid metabolism in SHRSP was compared with that in Wistar Kyoto rats (WKY). Phosphatidylinositol (PI) content was 20% less in SHRSP than in WKY, but no changes were observed in other phospholipids. Incorporation of [3H]-arachidonic acid (AA) into PI and phosphatidylethanolamine (PE) was 12% and 11% lower, and that into phosphatidylcholine (PC) was 6% higher in SHRSP than in WKY. Thrombin-induced diacylglycerol and phosphatidic acid formation were similar in both groups of platelets. Thrombin-induced release of [14C]-AA from the labeled platelets and its metabolism to eicosanoids occurred at similar rates. These results suggest that reduced formation of diacylglycerol, an activator of protein kinase C (PKC), does not cause defective phosphorylation of P47, a substrate of PKC, in SHRSP. However it remains unclear how the lower PI content and the altered distribution of AA in PC and PE is related to SHRSP platelet hypofunctions.

Animals↗
PubMed1991

Effects of the tumor inhibitor IKP-104, a 4(1H)-pyridinone derivative, on cytoskeletal microtubules of cultured tumor cells.

The effects of IKP-104, a 4(1H)-pyridinone derivative, on the mitotic profile and cytoskeletal microtubule dynamics of cultured B16 melanoma cells were examined in order to investigate the mechanism of its antitumor activity. The exposure to IKP-104 caused accumulation of cells in abnormal metaphase with chromosomes scattered within the cytoplasm and induced polyploid and multinucleate cells as detected by differential staining microscopy with brilliant blue R and safranin O. An immunofluorescence study with monoclonal anti-alpha-tubulin antibody revealed that IKP-104 diminished cytoskeletal microtubules of both interphase and mitotic cells, resulting in induction of a few fragments resembling "microtubular bundles" induced by vinblastine (VLB). These results indicated that IKP-104 arrests cells in the mitotic phase by inhibition of polymerization and induction of depolymerization of cytoskeletal microtubules, similarly to VLB.

Animals↗
PubMed1991

Production of aliphatic aldehydes on peroxidation of various types of lipids.

IN vitro peroxidation by air, or xanthine-xanthine oxidase (xanthine-XOD) was performed to estimate the production of aliphatic aldehydes from free polyunsaturated fatty acids (PUFA), triglycerides, phospholipids and rat liver microsomes and mitochondria. The aldehyde contents in peroxidized lipids were determined by liquid chromatography and fluorescence detection. In both peroxidation, pentanal, (E)-4-hydroxy-2-nonenal (4-HN), and hexanal were produced from omega-6 PUFA rich lipids and propanal was markedly enhanced by increasing the degree of fatty acid unsaturation. The ratios of 4-HN to hexanal production in xanthine-XOD peroxidation of the omega-6 PUFA rich lipids, and rat liver microsomes and mitochondria were much higher than those in air peroxidation. The ratios (4-HN/hexanal) obtained in microsomes and mitochondria by xanthine-XOD were similar to those in rat liver observed in vitamin E deficient studies. The determination of these aldehydes may be useful to estimate the kinds of fatty acids peroxidized and investigate in vivo lipid peroxidation mechanism.

Aldehydes↗
PubMed1991

Studies on eye irritation caused by chemicals in rabbits--II. Structure-activity relationships and in vitro approach to primary eye irritation of salicylates in rabbits.

Structure-activity relationships and in vitro evaluation of eye irritation potential of salicylates in rabbits were studied. The primary eye irritation potential of ten salicylates was evaluated according to Draize method. The effects of chemicals on model protein and lipid were investigated in vitro. The effects of chemicals on the protein could be detected by the production of aggregates of human serum gamma-globulin (HSG) and a good correlation was obtained between the ability of salicylates to produce aggregation of HSG and the potential of corneal irritation. The effects on the lipid could be detected by the adhesion potential of chemicals on lipid membrane and a linear correlation was not obtained between the adhesionary effects of salicylates on lipid membrane and the potential eye irritation. The corneal irritation and protein aggregation potential of salicylates were correlated with the acid dissociation constant more closely than octanol/water partition coefficient. The destruction of alpha-helix of proteins in corneal surface by salicylates were observed from the nondestructive structural analysis of corneal surface by Fourier Transform (FT)-IR spectroscopy. These results suggest that eye irritation caused by salicylates are mainly the results of denaturation of proteins in ocular tissue and that the effects on protein depend on the dissociation potential of molecules.

Animals↗
PubMed1991

Studies on eye irritation caused by chemicals in rabbits--II. An in vitro testing method using rat red blood cells for the prediction of eye irritation potential of chemicals.

Rat red blood cells were used as an in vitro method to evaluate the eye irritation potential of chemicals in rabbits. The results using 116 chemicals of various categories including medicines, pesticides, detergents and solvents were analyzed for the prediction of possibility of eye irritation potentials. Eye irritation of chemicals was examined according to Draize method and chemicals were classified into three categories, (1) non or mild irritants, (2) moderate or severe irritants and (3) strong or corrosive irritants, based on the recovery of damages. The in vitro method consisted of two methods detecting the effects of chemicals mainly on protein and lipid in the membrane, which were evaluated by the induction of methemoglobin and hemolysis, respectively. Non- or mild irritants induced neither methemoglobin formation nor hemolysis. Most of moderate or severe irritants induced hemolysis, however, the potentials were low. Strong or corrosive irritants had high potentials for the induction of methemoglobin. The multivariate estimation by the above two in vitro data sets were 77.6% predictive of the in vivo classification.

Animals↗
PubMed1990

A possible correlation between environmental chemicals and pigment cell neoplasia in fish.

A croaker (Nibea mitsukurii) has a high incidence of the skin melanoma, chromatophoroma, in a Pacific coastal area in Japan. A sea catfish (Plotosus anguillaris) bearing skin melanosis is also found in the same area. For elucidation of a correlation between these pigment cell neoplasms of the skin and environmental contaminants, an epidemiological survey was conducted to determine the distribution and prevalence of tumor-bearing fish. Based upon observations of a high prevalence of skin neoplasms near the discharge point for kraft pulp mills, experiments were conducted to determine the neoplastic induction efficiency of the effluent on the croaker and sea catfish species. Isolation and identification of mutagens in effluent extracts were carried out using the Ames test, followed by mass spectral analysis of mutagenic fractions. The effluent induced a chromatophoroma on one croaker of the 100 tested, and it induced pigment cell hyperplasia on 70 to 100% of the sea catfish. These skin neoplasms were grossly similar to those observed in the field. Five chloroacetones were identified from the Ames-positive fractions of the effluent, and tetrachlorocyclopentene-1,3-dione and two alpha-dicarbonyl compounds were also detected as mutagens. The above experiments indicate that the mutagenic contaminants found in kraft mill effluent may play an important role in the induction of skin neoplastic disease in fish.

Animals↗
PubMed1990

Antitumor activities of IKP-104, a 4(1H)-pyrizinone derivative, on cultured and implanted tumors.

Antitumor activities of IKP-104, a 4(1H)-pyrizinone derivative, were investigated with cultured tumor cell lines and implanted tumors in mice. IKP-104 inhibited the growth of cultured murine tumor cell lines (L1210 leukemia, Lewis lung carcinoma and B16 melanoma) and human tumor cell lines (K562 leukemia and HeLa cervical carcinoma). It also had antitumor effects on implanted murine ascitic tumors (L1210 leukemia and sarcoma 180) and a murine solid tumor (Lewis lung carcinoma). IKP-104 could be classified as a phase-dependent cytostatic drug based on the mode of growth inhibition of cultured B16 melanoma cells compared with those of several other antitumor agents. The effect of IKP-104 on the cell cycle traverse of cultured B16 melanoma cells was estimated by morphological and flow cytometric analyses. Cells accumulated in the mitotic phase, and abortive mitosis or polyploidy or multinucleation was induced from 6 h after exposure to IKP-104. Based on these results, IKP-104 is expected to be useful for the treatment of tumors, and its mode of action seemed to be similar to that of metaphase arrestants such as colchicine or vinca alkaloids.

Animals↗
PubMed1990

Studies on the formation of aliphatic aldehydes in the plasma and liver of vitamin E-deficient rats.

The effects of vitamin E (E) deficiency on the formation of aliphatic aldehydes in rat plasma and liver were studied. Three-week-old Wistar male rats were fed either an E supplemented diet (2-ambo-alpha-tocopheryl acetate 20 mg/kg diet, designated as E supplemented diet group) or an E deficient diet (E deficient diet group). After 8 weeks, n-hexanal and (E)-4-hydroxy-2-nonenal (4-HN) in the plasma of the E deficient diet group were found to be 2.0 and 2.5-fold greater than those of the E supplemented diet group, respectively. The contents of aldehydes such as n-pentanal, n-hexanal, 4-HN in the liver were also significantly higher in the E deficient diet group than in the E supplemented diet group. These results indicate that some aldehydes, arising possibly from lipid peroxides, are produced and detected in the plasma and liver of rats under the condition like E deficiency. In this study we further found that the activity of the liver aldehyde dehydrogenase (ALDH, EC 1.2.1.3) was significantly changed; 5 and 8 weeks after the start it was lower in the E deficient diet group when compared to that in the E supplemented diet group. The decrease of enzyme activity was related to the increase of aldehydes such as n-hexanal in the liver. the aldehyde increase in the plasma of the E deficient diet group was thought to raise the injury of cells, namely, a strong hemolysis on erythrocytes prepared from the blood of rats fed the E deficient diet.

Aldehyde Dehydrogenase↗
PubMed1990

Studies on eye irritation caused by chemicals in rabbits--1. A quantitative structure-activity relationships approach to primary eye irritation of chemicals in rabbits.

A quantitative structure-activity relationship (QSAR) approach has been applied to the analysis of the relation between the structural features of chemicals and the primary eye irritation in rabbits. One hundred thirty one heterogeneous chemicals including medicals, pesticides, detergents and organic solvents were used in this study. The eye irritation ratings were made in three classes on the basis of the recovery time of corneal and conjunctival damages. Thirty six descriptors were used to describe the molecules. To correlate eye irritation ratings with the descriptors, a QSAR model was formulated by the adaptive least-squares method. A three-class discrimination was made as follows; class I included 23 chemicals which induced the damages recovering within 24 hr, class II included 64 chemicals which induced the damages persisting for more than 24 hr but recovering within 21 days, class III included 44 chemicals which induced the damages not recovering within 21 days. The discriminant function included 18 descriptors. The accuracy in classifying the chemicals was 86.3% in the recognition and 74.0% in the leave-one-out prediction. These results suggest that QSAR analysis is valuable to predict the primary eye irritation of chemicals.

Animals↗
PubMed1989

Congenital changes of platelet functions in stroke-prone SHR: aggregability of gel-filtered platelets, PRP and whole blood, and effects of hypotensive treatment.

Platelet aggregation in whole blood, platelet rich plasma, and gel-filtered platelets were markedly attenuated in SHRSP compared with those in age-matched normotensive WKY. The result was consistent with the previous report of washed platelets. Despite prevention of high blood pressure, a long duration of hypotensive treatment only slightly improved aggregability of washed platelets but did not restore it to the range of age-matched WKY platelets. Blood pressure, heart ratios and thrombin-induced washed platelet aggregation were examined in SHRSP, WKY, and the cross (F1: WKY x SHRSP). The higher blood pressure and heart ratios the lower platelet aggregability was observed in the three strains, and there was no overlapping distribution of these values. F1 progeny exhibited intermediate values in blood pressure, heart ratio and platelet aggregability between the parental values. These results suggested that hypofunctions of SHRSP platelet were not secondary changes due to high blood pressure, but primary changes which are genetically linked to high blood pressure.

Animals↗
PubMed1989

Crude tea extracts decrease the mutagenic activity of N-methyl-N'-nitro-N-nitrosoguanidine in vitro and in intragastric tract of rats.

The effects of tea extracts and their ingredients, catechins and L-ascorbic acid (AsA), on the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were examined in vitro and in the stomachs of rats using E. coli WP2 and S. typhimurium TA100. The extracts of green tea and black tea leaves decreased the mutagenic activity of MNNG to E. coli WP2 in vitro in a desmutagenic manner. Catechins such as (-)-epigallocatechin from green tea leaves and the low-molecular-weight tannin fraction isolated from black tea extract with HP-20 resin also exhibited inhibitory effects against the mutagenic activity of MNNG. A desmutagenic effect of AsA on MNNG-induced mutagenicity was observed depending on the dose, though it was complicated. The effects were also demonstrated in the stomachs of rats by assaying the bacterial mutagenic in vitro; the tea extracts previously given orally to rats reduced the mutagenic activity of MNNG remarkably, though simultaneous administration showed less effect. The effectiveness of tea extracts for the decrease of MNNG-induced mutagenesis in vitro and in vivo suggests that the habitual drinking of tea may reduce the tumor-initiating potency of MNNG-type nitrosoureido compounds if they are formed in the stomach.

Animals↗