Biomedical subjects

T Imazawa

Publications and source records attributed to T Imazawa.

At least 37 records · Page 2Linked to original sources

PubMed1999

Failure of phenethyl isothiocyanate to inhibit hamster tumorigenesis induced by N-nitrosobis(2-oxopropyl)amine when given during the post-initiation phase.

The chemopreventive influence of phenethyl isothiocyanate (PEITC) during the post-initiation stage was investigated in the N-nitrosobis(2-oxopropyl)amine (BOP)-initiated hamster tumorigenesis model. A total of 120 female 5-week-old hamsters were divided into six groups. Animals in groups 1-3, each consisting of 30 hamsters, were injected twice, subcutaneously, with BOP 7 days apart to effect initiation. Starting 1 week after the second BOP injection, hamsters in groups 1 and 2 were fed diets supplemented with 6 micromol/g and 3 micromol/g of PEITC, respectively, for 51 weeks. Animals in group 3 received a basal diet as an initiation positive control. Animals in groups 4-6, each consisting of ten hamsters, were given 6 micromol/g or 3 micromol/g of PEITC alone, or were non-treated, matched negative controls for groups 1-3. At the termination of experimental week 52, the incidences and multiplicities of neoplastic lesions in the target organs including the pancreas, lung, liver and kidney were found to be comparable among the BOP-treated groups. The values for pancreatic adenocarcinomas as well as dysplastic lesions tended to increase although without statistical significance. Taken together with our previous finding that PEITC dramatically inhibited the initiation phase of BOP-induced pancreatic and lung tumorigenesis in hamsters, it can be concluded that PEITC specifically exerts chemopreventive effects only when given concomitantly with the carcinogen.

Adenocarcinoma↗

PubMed1999

The relationship between decrease in Cx32 and induction of P450 isozymes in the early phase of clofibrate hepatocarcinogenesis in the rat.

To examine the relationship between the decrease in connexin 32 (Cx32) and induction of P450 isozymes in the early phase of clofibrate hepatocarcinogenesis, a total of 20 male F344 rats were initiated with a single intraperitoneal injection of 150 mg/kg of diethylnitrosamine (DEN) or given the saline vehicle alone and starting 2 weeks later given diet containing 0.18, 0.09, and 0% clofibrate for 6 weeks. All animals were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Absolute and relative (ratios to body weight) liver weights were significantly increased in the DEN + clofibrate groups compared with the DEN-alone group. Diffuse hepatocellular hypertrophy with granular cytoplasmic eosinophilia characterized by a marked increase in peroxisomes and smooth endoplasmic reticulum, was observed in the clofibrate treated rats. Induction of cytochrome P450 (CYP) 4A1 and 2B1/2 was noted in the DEN + clofibrate groups, this being most marked in the CYP 2B1 case. Immunohistochemically, positive immunostaining for anti-CYP 4A1 and CYP 2B1 were observed diffusely and centrilobularly, respectively. The numbers and areas of Cx32-positive spots per hepatocyte in the centrilobular areas in the treated rats were significantly decreased in an essentially dose-dependent manner, but no changes were observed in periportal areas. The numbers and areas of foci positive for glutathione S-transferase placental form (GST-P) were decreased in a dose dependent manner in the clofibrate treated groups. These results suggest that the CYP 2B1/2 induction and Cx32 decrease in centrilobular hepatocytes, similarly to those thought to be involved in the hepatic promotion mechanism of phenobarbital, may also play important roles in clofibrate actions in the liver, in addition to its causation of oxidative DNA injury.

Animals↗

PubMed1999

Suppressive effects of josamycin on the development of altered liver cell foci and chronic nephropathy in a carcinogenicity study.

The carcinogenicity of josamycin was examined in Fischer 344 (F344) rats. Groups of 50 males and 50 females were given the compound in their diet at concentrations of 0 (control), 1.25 or 2.5% for 104-weeks; these dose levels were selected on the basis of the results of a subchronic study, in which animals rather rejected 5% josamycin. All surviving rats were killed at wk 106. A variety of tumours developed in all groups, including the control group, but all the neoplastic lesions were histologically similar to those known to occur spontaneously in this strain of rats, and no statistically significant increase in the incidence of any tumour was found in the treated groups of either sex. Interestingly, the josamycin treatment significantly reduced the development of altered liver cell foci and chronic nephropathy in a dose-dependent manner. Thus, it was concluded that, under the present experimental conditions, josamycin is not carcinogenic in F344 rats.

Animals↗

PubMed1999

[A 13-week subchronic toxicity study of D-xylose in F344 rats].

A 13-week subchronic toxicity study of D-xylose was performed in male and female F344 rats at dose levels of 0%, 0.2%, 0.6%, 1.7%, and 5% D-xylose in the CRF-1 powder diet to determine the maximum tolerable dose (MTD) for subsequent investigation of carcinogenicity. Rats were randomly allocated to 5 groups each consisting of 10 males and 10 females. Rats were randomly allocated to 5 groups each consisting of 10 males and 10 females. No treated groups showed changes in body weight gain or food intake, and all animals survived until the end of the experiment. Hematological examination revealed significant increases in RBC, Hb, and Ht in the male groups treated with 0.6% and 5% concentrations, whereas these values decreased significantly in all of the female groups treated with D-xylose. However, no clear dose-response effect was observed in the hematological data in either males or females given D-xylose. Serum biochemistry studies revealed decreases in AsT in the 0.2% and 5% D-xylose group male and 0.2%, 1.7%, and 5% group female, compared to the control value. However, the changes were not considered specific because of the lack of any clear dose-response effect. In addition, no histopathological changes indicating obvious toxicity of D-xylose were observed in the livers of either sex treated with D-xylose. Based on these data, the MTD of D-xylose in F344 rats of both sexes is judged to be 5% or more in the diet.

Administration, Oral↗

PubMed1999

[A 90-day subchronic oral toxicity study of Bacillus subtilis gum in F344 rats].

A 90-day subchronic toxicity study of Bacillus subtilis gum was performed in both sexes of F344 rats by feeding of CRF-1 pellet diet containing 0%, 0.18%, 0.55%, 1.66% and 5%. Rats were randomly allocated to 5 groups, each consisting of 10 males and females. No animals died during the administration period and no differences in body weights and food intakes were found among groups of either sex. Kidney weight was significantly increased in both sexes in the groups given concentrations of 1.66% or more. However, the increases of kidney weight were slight in themselves and other data on serum biochemistry and histopathology did not show any apparent toxicological signs including renal toxicity. These findings indicate that the treatment of Bacillus subtilis gum in the diet for 90 days does not exert serious toxicity in rats even at the highest dose.

Animals↗

PubMed1999

[A 13-week subchronic oral toxicity study of orange color in F344 rats].

A 13-week subchronic toxicity study of orange color was performed in both sexes of F344 rats by feeding them a CRF-1 powder diet containing 0%, 0.18%, 0.55%, 1.66%, and 5% concentrations of the substance. No animals died during the administration period, and no changes in body weight or food intake were found in any of the dosage groups. There were significant increases in serum cholesterol in males given 1.66% or higher concentrations of orange color and in females given 0.55% or higher concentrations, and significant increases in alkaline phosphatase in males given 1.66% or higher concentrations, possibly due to the high-fat composition of the orange color diets. In addition, some hematological, serum biochemical, and histopathological changes were observed in the groups given greater than 0.55% concentrations, but they did not suggest obvious toxicity. These findings indicate that under these experimental conditions the no-observed-effect level (NOEL) of orange color in the diet for 13 weeks is 0.18% and the no-observed-adverse-effect level (NOAEL) is 5%.

Administration, Oral↗

PubMed1998

Ultrastructural changes in motor endplates of the lumbrical muscles of rats induced by a microsomal Ca2+ ATPase inhibitor, 2,5-di(tert-butyl)-1,4-hydroquinone.

Female Wistar rats were treated orally for 5 days with 80 mg/kg body weight of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ), a microsomal Ca2+ ATPase inhibitor. Motor endplates of the lumbrical muscles were examined by light and electron microscopy. There was a decrease in body weight in the treated rats from the first day after administration, and toxic signs appeared after the third day, such as adoption of a prone position, salivation, lacrymation, and an abnormal gait and/or muscle weakness. No remarkable macroscopic or light microscopic changes were noted in the lumbrical muscles as well as other peripheral nerves of hind legs of the treated rats killed 1 day after the last DTBHQ treatment. Ultrastructurally, neurotoxicity characterized by loss of synaptic vesicles and mitochondria in the motor endplates, and by destruction of the motor terminals was detected in the lumbrical muscles of the treated rats. These results strongly indicate that DTBHQ targets the motor endplates in the rat lumbrical muscles and suggest that the resultant damage is responsible for the appearance of neurological signs, such as an abnormal gait and loss of muscle control.

Administration, Oral↗

PubMed1998

Mechanistic study on liver tumor promoting effects of piperonyl butoxide in rats.

Piperonyl butoxide, alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltol uene, is a widely used pesticide-synergist. Recently, results were reported indicating that piperonyl butoxide is a hepatocarcinogen in rat. Since the underlying mechanism was not elucidated, we examined the effects on rat liver cells in detail. For this purpose male F344 rats were administered piperonyl butoxide mixed in the diet at concentrations of 0 (negative control), 0.05, 0.2 or 2% for 2 days, 1, 2, and 4 weeks. As a positive control, phenobarbital was administered to rats for up to 4 weeks as a 0.1% solution in the drinking water. Increased liver weight, centrilobular hepatocellular hypertrophy due to increased smooth endoplasmic reticulum, decreased numbers and areas of connexin 32-positive spots per hepatocyte, and increased cell proliferation were observed in rats treated with 0.2 and 2% piperonyl butoxide. Similar results were obtained for 0.1% phenobarbital treated rats. Hepatocellular necrosis suggestive of hepatotoxicity was also observed in the 2% piperonyl butoxide group. These results indicate that the promoting mechanism of piperonyl butoxide in hepatocarcinogenesis is similar to that of phenobarbital, involving an ability to induce CYP isoenzymes and inhibit gap junctional intercellular communication. In addition, increased cell proliferation following hepatocellular necrosis may also play a role at high doses.

Animals↗

PubMed1998

Enhancing effects of quinacrine on development of hepatopancreatic lesions in N-nitrosobis(2-oxopropyl)amine-initiated hamsters.

The modifying effects of quinacrine administration during the post-initiation phase of carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Female Syrian hamsters were given three weekly s.c. injections of BOP at a dose of 10 mg/kg and then 300 or 100 ppm quinacrine in their diet for 37 weeks. Additional groups of animals received the BOP injection alone, or only the 300 ppm quinacrine treatment as BOP-negative controls. At week 40 of the experiment, all surviving animals were killed and development of proliferative lesions was assessed histopathologically. The multiplicity of pancreatic adenocarcinomas and dysplastic lesions per hamster was significantly higher (P<0.01 and P<0.05) in the BOP/Q100 group (1.92 and 1.78) than in the BOP-alone group (1.07 and 0.79). The incidence of hepatocellular adenomas plus carcinomas was also significantly elevated (P<0.05) in the BOP/Q300 and BOP/Q100 groups. In contrast, the multiplicity of lung adenomas plus adenocarcinomas was significantly decreased (P<0.05) by the Q300 treatment. Neither the incidence nor the multiplicity of renal cell tumors (adenomas and carcinomas) or nephroblastomas significantly differed between the BOP-treated groups. Electron microscopic examination revealed an abundance of myeloid lamellar bodies filling the cytoplasm of hepatocytes and pancreatic ductular and acinar cells, and epithelial cells of the gallbladder in the quinacrine-treated animals, the degree being dose-dependent. Our results indicate that quinacrine enhances pancreatic and hepatic carcinogenesis in hamsters induced by BOP.

Animals↗

PubMed1998

[A 13-week subchronic oral toxicity study of chlorophyll in F344 rats].

A 13-week subchronic toxicity study of chlorophyll (containing 40% oil) was performed in both sexes of F344 rats by feeding of CRF-1 powder diet containing 0, 0.18%, 0.55%, 1.66% and 5%, and vehicle (oil) alone. No animals died during the administration period and no changes in body weights and food intakes were found in any dosed groups. Some hematological, serum biochemical and histopathological changes were observed for the 5%-treated group, but these did not suggest obvious toxicity. These findings indicate that the treatment with 1.66% chlorophyll in diet for 13 weeks does not cause any changes in rats and the 5% feeding is not obviously toxic.

Animals↗

PubMed1997

Failure of dietary alpha-difluoromethylornithine to inhibit gastric carcinogenesis in rats after 8 weeks of treatment with N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride.

The modifying effects of alpha-difluoromethylomithine (DFMO) on glandular stomach carcinogenesis after initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride were investigated in male outbred Wistar rats. Animals were simultaneously given MNNG solution (100 ppm) as their drinking water and diet supplemented with 10% sodium chloride for 8 weeks, and administered DFMO (dietary levels of 2000 ppm or 500 ppm) and tap water for the following 70 weeks. The DFMO treatment did not show any tendency to inhibit the development of gastric adenocarcinomas. The incidences and multiplicities of atypical hyperplasias in the glandular stomachs were also comparable in all groups of rats given MNNG/sodium chloride. Neither gastric carcinomas nor atypical hyperplasias were observed without the carcinogen treatment. Thus, DFMO did not exert any inhibitory effects when given during the post-initiation phase of two-stage glandular stomach carcinogenesis in rats initiated with MNNG and sodium chloride for 8 weeks.

Adenocarcinoma↗

PubMed1997

Liver tumour-promoting effects of oxfendazole in rats.

To examine whether oxfendazole has tumour-promoting activity, a total of 100 male Fisher 344 rats were initiated with a single ip injection of 100 mg/kg of diethylnitrosamine (DEN) or given saline vehicle alone and starting 1 wk later given diet containing 500, 250, 100, 10 or 0 ppm of oxfendazole for 8 wk. Sub-groups of five rats each from the DEN plus 250 and 0 ppm groups were killed after wk 1 of oxfendazole treatment and the remaining animals at wk 8. At the termination relative liver weights were significantly increased in the DEN-initiated and non-initiated groups treated with 250 ppm and 100 ppm or more, respectively, compared with the corresponding controls values. Light microscopical examination showed centrilobular hepatocellular hypertrophy in all animals receiving 100 ppm or more. Electron microscopy also revealed marked increases in smooth endoplasmic reticulum in hepatocytes of the DEN plus 500 ppm group. Furthermore, induction of cytochrome P-450 (CYP) 1A1/2, 2B1/2 or 4A1 was observed in the DEN plus 100 ppm group, that of CYP 1A1/2 being most marked. A similar change in CYP 1A1/2 was seen in the DEN plus 10 ppm group. The numbers and areas of connexin 32 (Cx32)-positive spots per hepatocyte were also significantly decreased in a dose-dependent manner. Similar changes in liver weights, P-450 isozymes and Cx32 immunohistochemistry were already evident in the DEN plus 250 ppm group at wk 1. The number of placental form glutathione S-transferase positive single cells was significantly increased in the DEN-initiated groups treated with 250 ppm or more. The results therefore strongly suggest that oxfendazole exerts liver tumour promotion potential.

Administration, Oral↗

PubMed1997

[Effects of dietary magnesium deficiency in the rat: with special reference to ultrastructural examination].

Epidemiologically, it has been suggested that dietary magnesium/calcium imbalance is associated with the risk of heart diseases. In the present study, the effects of magnesium deficiency and/or calcium over intake were investigated in rats. Male Sprague-Dawley rats were divided into 4 groups, and respectively fed basal diet (AIN-76) alone (Group 1), calcium-doubled AIN-76 diet (Group 2), magnesium-deficient AIN -76 diet (Group 3) and magnesium-deficient/calcium-doubled AIN-76 diet (Group 4) for 19 days. A biochemical assay using inductively coupled plasma showed that the magnesium concentrations of the femoral bone and serum were significantly (p < 0.001) lower in Groups 3 and 4 than in Group 1. The lipid peroxides of the heart in Group 4 and of the liver in Groups 3 and 4 were increased as compared to the Group 1 values although there was no statistical significance. Ultrastructurally, degenerative changes of organellas including mitochondria were observed in myocardial, liver and renal tubule cells of Groups 2-4. Severe degeneration such as disorganization, lysis and disarrangement of myofibrils was most evident in myocardial cells of Group 4. Our results thus suggest that dietary magnesium deficiency gives rise to retrogressive changes in some organs including the heart, and concurrent calcium overintake synergistically enhances the myocardial injury due to magnesium deficiency.

Animals↗

PubMed1996

Quantitative analysis of vascular endothelial growth factor in primary breast cancer.

BACKGROUND: Recent clinical studies have demonstrated that tumor angiogenesis is a potent prognostic indicator for breast cancer patients. The quantitation of endothelial growth factors is thought to be useful to assess angiogenic phenotype in the tumor. Among the many new endothelial growth factors, vascular endothelial growth factor (VEGF) is known to be particularly responsible for promoting the neovascularization in human breast cancer. METHODS: Intratumoral protein levels of VEGF were measured by enzymatic immunoassay in 135 primary breast cancer tissues. The VEGF levels were compared with the microvessel density evaluated by immunostaining the endothelial antigen and also were compared with intratumoral protein levels of other endothelial growth factors, including basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF). RESULTS: Intratumoral VEGF concentrations varied from 3.3 pg/mg protein to 2032 pg/mg protein (average 148 pg/mg protein). An immunocytochemical analysis using anti-VEGF antibody confirmed that VEGF was located mainly in the cytoplasm of the tumor cells. The VEGF concentrations were significantly higher in vascularly rich tumors than in vascularly poor tumors. No significant association was found between VEGF concentrations and the two other endothelial growth factor concentrations. CONCLUSIONS: The quantitation of intratumoral VFGF levels seems to be useful for assessing the activity of tumor angiogenesis.

Breast Neoplasms↗

PubMed1996

Long-term toxicity/carcinogenicity study of L-histidine monohydrochloride in F344 rats.

The long-term toxicity and carcinogenicity of histidine, an essential amino acid for most animal species, were examined in Fischer 344 (F344) rats. Groups of 50 males and 50 females were given L-histidine monohydrochloride (HMHC) in their diet at concentrations of 0 (control), 1.25 and 2.5% for 104 wk; these dose levels were selected on the basis of the results of a subchronic toxicity study, in which body weights were depressed and formation of sperm granulomas in the epididymis was histologically evident in males fed 5.0% HMHC. All surviving rats were killed at wk 107. Increases in red blood cell count, haemoglobin value and haematocrit level were observed in male rats given 2.5% HMHC. A variety of tumours developed in all groups, including the control group, but all the neoplastic lesions were histologically similar to those known to occur spontaneously in this strain of rats, and no statistically significant increase in the incidence of any tumor was found in the treated groups of either sex. Thus, it was concluded that, under the present experimental conditions, HMHC is not carcinogenic in F344 rats.

Administration, Oral↗

PubMed1996

Inhibitory effects of the dietary antioxidants butylated hydroxyanisole and butylated hydroxytoluene on bronchioloalveolar cell proliferation during the bleomycin-induced pulmonary fibrosing process in hamsters.

The effects of dietary antioxidants on bleomycin (BLM)-induced pulmonary fibrosis were investigated in Syrian golden hamsters. In addition, the influence on cell proliferative activity in bronchioloalveolar hyperplastic lesions during the lung fibrosing process was evaluated in terms of argyrophil nucleolar organizer regions (AgNORs) and proliferating cell nuclear antigen (PCNA). Male 6-wk-old hamsters were divided into six groups. Groups 1-3 were intratracheally instilled with BLM at a dose of 2.5 U/kg body weight on days 0 and 14, and then given a diet supplemented with 1% butylated hydroxyanisole (BHA), or 1% butylated hydroxytoluene (BHT), or basal diet alone for the following 41 days. Groups 4-6 were given 1% BHA, 1% BHT or basal diet without BLM treatment for the same time period as that in those of groups 1-3. The mortality rate of animals in group 1 (BLM/BHA) (one in 20; 5%) was lower than in those of groups 2 (BLM/BHT) (three in 20; 15%) and 3 (BLM alone) (four in 20; 20%). BHA and BHT treatments significantly inhibited lung weight gains by BLM (P < 0.05). Histopathologically, both BHA and BHT reduced BLM-induced pulmonary histopathological changes such as fibrosis, macrophage aggregation and epithelial proliferation, with a tendency for correlation with accumulation of type III collagen. In addition, antioxidant treatment significantly lowered the mean numbers of AgNORs (P < 0.01) and PCNA-labelling indices (P < 0.05) in the hyperplastic bronchioloalveolar lesions. The results thus indicate that these antioxidants exert inhibitory effects on proliferation of hyperplastic lesions associated with lung fibrosis.

Animals↗

PubMed1996

Ultrastructure and cell proliferative activities of karyomegalic alveolar epithelial cells in early pulmonary inflammatory lesions of Syrian golden hamsters induced by N-methyl-N-nitrosourethane.

To clarify the biological behavior of karyomegalic alveolar epithelial cells induced by N-methyl-N-nitrosourethane (MNUR) and whether these cells progress to lung tumors, female Syrian golden hamsters, 6 weeks old, were given five subcutaneous injections of 0.6 mg/animal of MNUR at two week intervals and their lungs were examined at weeks 1, 4, 8 and 12 after the termination of treatment. At week 1, in severely affected areas where marked multifocal thickening of alveolar walls due to interstitial edema and cellular infiltration was observed, some regenerative alveolar epithelial cells had abundant eosinophilic cytoplasm and gigantic bizarre nuclei. The cells were confirmed ultrastructurally to be derived from alveolar type II cells. The number of these karyomegalic epithelial cells became significantly decreased thereafter, together with the reduction of inflammatory changes. On AgNOR staining, normal alveolar epithelial cells had 1.8 +/- 0.03 black dots within their nuclei while the karyomegalic epithelial cells had 4 black dots or more, from 1 week. The PCNA labeling index of the karyomegalic epithelial cells at week 1 was 14.6 +/- 2.4, and was significantly decreased from 4 week. This epithelial cell population also displayed a wider range of DNA contents (2.1-5.5C) than normal epithelial cells (1.6-2.3C). These results suggest that karyomegalic alveolar epithelial cells may be mutant cells which occur after initiation with MNUR, but the possibility that they can act as progenitors of alveolar epithelial cell tumors was considered to be extremely low.

Animals↗

PubMed1996

[A 13-week subchronic toxicity study of gardenia blue in F344 rats].

A 13-week oral toxicity study of gardenia blue was performed in male and female F344 rats at the dose levels of 5.0, 2.5, 1.25, 0.6 and 0% in the diet, to determine the maximum tolerable dose (MTD) for subsequent investigation of carcinogenicity. Rats were randomly allocated to 5 groups, each consisting of 10 males and 10 females. No groups showed decreases in body weight gain and food intake, and all animals survived until the end of the experiment. A dose-dependent decrease in number of platelets was observed in females treated with gardenia blue in hematological examination, but not in males. No histopathological change, relating to the treatment, in megakaryocyte which is the progenitor cell of platelets was observed in the treated-females. Serum biochemistry revealed increases in GOT and GPT in both sexes treated with the 5.0% and 2.5% gardenia blue, as compared to the control value. However, these were not considered to be specific changes because of lack of any clear dose response. In addition, no histopathological changes indicating obvious toxicity of gardenia blue were observed in the liver of both sexes treated with gardenia blue. Based on these data, the MTD of gardenia blue for both sexes in F344 rats was considered to be 5.0% or more in the diet.

Alanine Transaminase↗