[On surgery of idiopathic esophageal dilatation].
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Adult↗
Biomedical subjects
M Hirose
Publications and source records attributed to M Hirose.
[Experimental pulmonary reimplantation].
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Angiography↗
Pharmacokinetics of [125I]-recombinant human interleukin-11: 1. Absorption, distribution and excretion after subcutaneous administration to male rats.
Absorption, distribution, metabolism and excretion of [125I]-rhIL-11 (recombinant human interleukin-11) after subcutaneous administration in rats were investigated. After a single administration, the concentration of radioactivity in the tissues was 2-6-fold higher in the liver and kidneys, and slightly higher in the gastrointestinal tract as compared to the plasma concentration. However, since the concentration in the other tissues was lower than the plasma concentration, the transport of rhIL-11 into tissues appeared to be low. Tissue radioactivity rapidly diminished, thus accumulation of rhIL-11 in tissues was thought to be low. Excretion of radioactivity into urine and feces was almost complete 72 h after administration, with 88.5% of the dosed radioactivity being found in urine and 7.9% in feces. When [125I]-rhIL-11 was administered to bile-duct cannulated rats, 44.4% of the dosed radioactivity was excreted into bile up to 48 h after administration. Most radioactivity in bile and urine was found in the TCA supernatant and low molecular weight fraction by HPLC analysis, indicating that rhIL-11 was eliminated from the body by metabolism.
Animals↗
Pharmacokinetics of [125I]-recombinant human interleukin-11: 2. Placental transfer and excretion into milk after subcutaneous administration to rats.
Placental transfer and excretion into milk of [125I]-rhIL-11 (recombinant human interleukin-11) after subcutaneous administration in female rats were investigated. After administration of [125I]-rhIL-11 to rats on the 14th day of gestation, radioactivity in the kidney was the highest among excised tissues, being 3 times higher than that in the plasma at 1.5 h. Radioactivity in other tissues, including the mammary gland, ovary, uterus, placenta and amniotic fluid, was lower than that in the plasma. Although radioactivity in fetuses was detected 6 h after administration, the level was only 2% of the plasma concentration in dams, and the radioactivity was not found in fetal-derived TCA precipitates. These results indicate that rhIL-11 does not readily pass through the placenta into the fetus. After subcutaneous administration of [125I]-rhIL-11 to lactating rats 14 days after delivery, radioactivity in milk was 1.1-1.6 times that in the plasma of dams. Radioactivity in clotted milk in the stomachs of suckling infants was almost equal to that in the dam's milk; however, only a small amount of radioactivity was detected in infant kidneys.
Animals↗
Doxorubicin induces male germ cell apoptosis in rats.
To clarify whether apoptosis is involved in doxorubicin (DXR)-induced testicular toxicity and to identify the target germ cell type, adult Sprague-Dawley rats were treated with a single intravenous dose of DXR (8 or 12 mg/kg) and euthanized at 3, 6, 12, 24, and 48 h subsequently. Histologically, germ cell degeneration was first found 6 h after dosing in meiotically dividing spermatocytes and early round spermatids of seminiferous tubules at stage 1, and subsequently observed in spermatogonia at stages I-VI showing ultrastructural characteristics of apoptosis. Coincident with the appearance of morphological changes, degenerating germ cells were shown to be undergoing apoptosis as revealed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The frequency of TUNEL-labeled germ cells increased in a stage- and cell type-specific manner, the peak of frequency gradually progressing from stage I of seminiferous tubules to later stages with time after dosing, suggesting that the damaged germ cells, especially spermatogonia, gradually underwent the processes leading to apoptosis. DNA laddering on gel electrophoresis was apparent 24 and 48 h after dosing. The results demonstrate that apoptosis plays an important role in the induction of testicular toxicity caused by DXR with meiotically dividing spermatocytes and type A and intermediate spermatogonia as highly vulnerable target cells.
Animals↗
Studies on antioxidants: their carcinogenic and modifying effects on chemical carcinogenesis.
Studies were conducted on the carcinogenic activity of butylated hydroxyanisole (BHA) in rats and hamsters. To obtain information concerning the mechanism of action of BHA on the forestomach, the following areas were examined: the effects of 12 phenolic compounds structurally related to BHA on the hamster forestomach, the effects of combinations of BHA and other antioxidants on the rat forestomach, and the metabolism of BHA in the forestomach. Also examined were the effects of several antioxidants on two-stage carcinogenesis in rats. Squamous-cell carcinomas were induced in the forestomach of rats and hamsters fed BHA. In a limited study, 1 of 13 hamsters developed a squamous-cell carcinoma. The tumorigenic action of crude BHA on the forestomach was largely due to the action of 3-tert-BHA. p-tert-Butylphenol and 2-tert-butyl-4-methylphenol induced pronounced hyperplasia and papillomas in the hamster forestomach. BHA and other antioxidants, particularly propyl gallate and ethoxyquin, showed additive effects in inducing forestomach hyperplasia and cytotoxicity. Neither BHA nor its metabolites were found in the forestomach epithelium, although small amounts of metabolites were detected in the stomach contents. Thus, a direct action on the stomach epithelium may be exerted by BHA itself or by metabolites formed on interaction of BHA with gastric juice. BHA enhanced forestomach carcinogenesis initiated in rats by N-methyl-N'-nitro-N-nitrosoguanidine or N-methylnitrosourea (MNU) and enhanced urinary bladder carcinogenesis initiated by MNU or N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). In contrast, it inhibited carcinogenesis initiated in the liver by either diethylnitrosamine or N-ethyl-N-hydroxyethylnitrosamine (EHEN) and mammary carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene (DMBA). BHT promoted urinary bladder carcinogenesis initiated by BBN or MNU and thyroid carcinogenesis initiated by MNU, but inhibited ear-duct carcinogenesis initiated by DMBA. Ethoxyquin promoted EHEN-initiated kidney carcinogenesis, but inhibited both DMBA-initiated mammary and EHEN-initiated liver carcinogenesis. Sodium ascorbate promoted forestomach and urinary bladder carcinogenesis, and sodium erythorbate also enhanced urinary bladder carcinogenesis. alpha-Tocopherol inhibited ear-duct carcinogenesis. No antioxidants tested had any effect on glandular stomach carcinogenesis. Thus antioxidants have independent modifying (promoting or inhibitory) effects in different organs.
Administration, Oral↗
Quantitative analysis of initiating and promoting activities of five mycotoxins in liver carcinogenesis in rats.
The initiating and promoting activities of several mycotoxins were investigated in F344 male rats. N-2-Fluorenylacetamide (2-FAA) was used as an initiator or a promoter and citrinin, ochratoxin A, sterigmatocystin, (+)rugulosin or patulin was administered at a fixed dose for the same period in the initiation stage or the promotion stage. Partial hepatectomy and administration of carbon tetrachloride (CCl4) were examined to increase the induction of hyperplastic nodules. Ochratoxin A, sterigmatocystin and (+)rugulosin administered in either the initiating or the promoting stage significantly increased the induction of hyperplastic nodules. Citrinin and patulin administered in the initiating stage significantly increased the induction of hyperplastic nodules, but were not effective when administered during the promoting stage. The theoretical classification of the mycotoxins examined is discussed.
Animals↗
Inhibition of glutathione S-transferase P type-positive foci development by linolic acid hydroperoxides and their secondary oxidative products in a rat in vivo mid-term test for liver carcinogens.
The effects of linolic acid hydroperoxides (product A) and secondary oxidative products of product A (product B), were examined in an in vivo mid-term test for hepatocarcinogens or hepatopromoters in rats. The number of placental type of glutathione S-transferase (GST-P)-positive foci of the liver was significantly reduced in rats given diethylnitrosamine (DEN) followed by products A (4.64 +/- 1.09, P less than 0.05) or B (3.62 +/- 1.65, P less than 0.01) as compared to the controls given carcinogen alone (6.31 +/- 2.82). The area of GST-P positive foci was also significantly reduced in rats given DEN followed by product B (0.30 +/- 0.21, P less than 0.05) as compared to the controls (0.47 +/- 0.23). These results suggest that linolic acid hydroperoxides or their secondary oxidative products are not hepatocarcinogens and rather may possess inhibitory potential for liver carcinogenesis.
Animals↗
Enhancement of hepatocarcinogenesis by combined administration of food-derived heterocyclic amines at low doses in the rat.
Effects of simultaneous administration of five or 10 heterocyclic amines (HCAs) at low dose levels on rat liver carcinogenesis were investigated using a medium-term bioassay protocol. Male F344 rats were initially given diethylnitrosamine (DEN, 200 mg/kg, ip) and received HCAs starting 2 wk later for 6 wk. All animals were subjected to two-third partial hepatectomy at wk 3 and were killed at wk 8. Five carcinogenic HCAs in the first two experiments: 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-aminodipyrido[1,2-alpha: 3',2'-d]imidazole, 2-amino-3-methylimidazo-[4,5-f]quinoxaline, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline in experiment 1 and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, 2-amino-6-methyl-dipyrido[1,2-alpha: 3',2'-d]imidazole,2-amino-3-methyl- 9H-pyrido-[2,3-b]indole, 2-amino-9H-pyrido[2,3-b]indole, and 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine in experiment 2] were administered together or individually in the diet at levels of 1/1, 1/5 or 1/25 carcinogenic doses, and all 10 chemicals were given at 1/10 or 1/100 levels in experiment 3. Induction of preneoplastic glutathione S-transferase placental from (GST-P) positive foci was increased in some combination groups over the sums of effects for the individual groups at the same doses (apparent synergism). This was most obvious in the group given all 10 chemicals at the 1/10 dose levels. However, it was of interest that the values in the combined groups were generally very close to the averages of five or 10 individual results for the corresponding higher dose groups, indicating isoadditivity of HCA effects. True (strict) synergism, however, was expected for the results of groups including PhlP and Trp-P-2 in combination, since they are non-hepatocarcinogenic but induce the key metabolic enzyme for HCAs (CYP1A2).
Administration, Oral↗
Phenolics: blocking agents for heterocyclic amine-induced carcinogenesis.
Chemopreventive effects of synthetic and naturally occurring antioxidants on heterocyclic amine (HCA)-induced rat carcinogenesis and mechanisms of inhibition were assessed. In a medium-term liver bioassay, combined treatment with 0.03% 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and synthetic antioxidants such as 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), butylated hydroxyanisole (BHA), butylated hydroxutoluene (BHT), tert-butylhydroquinone (TBHQ) or propyl gallate, each at a dose of 0.25%, inhibited development of preneoplastic glutathione S-transferase placental form (GST-P) positive foci as compared with MeIQx alone, after initiation with diethylnitrosamine (DEN). Of these antioxidants, HTHQ showed the greatest activity. 8-Hydroxydeoxyguanosine (8-OHdG), a marker for DNA damage induced by active oxygen species, and malonedialdehyde and 4-hydroxynonenal levels were not largely influenced by the treatment with MeIQx or antioxidants, either alone or in combination. In the same medium-term liver bioassay, effects of some naturally occurring antioxidants, such as green tea catechins (GTC), hesperidin, chlorogenic acid, quercetin, rutin, curcumin, daidzin, ferulic acid and genistein were also examined. Of these antioxidants, only GTC tended to inhibit GST-P positive foci development, while quercetin, rutin, curcumin, daidzin, ferulic acid and genistein all exerted significant enhancing effects. Examination of HTHQ influence in a medium term liver bioassay with HCA Glu-P-1, in which the experimental period was extended for up to 26 weeks, also demonstrated a significant decrease in the incidence of liver tumours to 40% in the group treated with 0.5% HTHQ and 0.03% 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) as compared with the Glu-P-1 alone value of 89%. Effects of HTHQ on colon carcinogenesis induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were evaluated in a two-stage colon carcinogenesis model using 1,2-dimethylhydrazine (DMH) as an initiator. At week 36, the multiplicity of colon tumours induced by 0.02% PhIP after DMH initiation (9.1+/-6.2/rat) was dose-dependently decreased by the combined treatment with 0.5% HTHQ (3.6+/-1.8, P < 0.001) and 0.125% HTHQ (6.2+/-3.2, not significant). Similarly, the incidence of mammary carcinomas in female F344 rats induced by oral administration of 0.02% PhIP (40%) for 52 weeks was significantly decreased by simultaneous treatment with 0.5% HTHQ (5%). Alpha-tocopherol and chlorophyllin only reduced the multiplicity of carcinomas. Analysis of the influence of HTHQ on metabolic activation of Glu-P-1 or PhIP after incubation with rat S9 mixture and NADPH by HPLC, revealed that each major metabolite was strongly reduced by the addition of HTHQ. Immunohistochemically detected PhIP-DNA adduct positive nuclei in the colon induced by continuous oral treatment with 0.02% PhIP for 2 weeks decreased by the combined treatment with 0.5 or 0.125% HTHQ. These results indicate that synthetic antioxidant HTHQ is a very strong chemopreventor of heterocyclic amine (HCA)-induced carcinogenesis and that depressed metabolic activation rather than antioxidant activity is responsible for the observed effect.
Animals↗
Lack of carcinogenicity and increased survival in F344 rats treated with 5-fluorouracil for two years.
The carcinogenicity of 5-fluorouracil (5-FU), a compound employed as an antineoplastic drug, was investigated in F344 rats of both sexes. 5-FU was administered to groups of 50 male and 50 female rats ad lib. for 104 weeks, added to drinking water at concentrations of 0 (control), 62 and 125 ppm, these dose levels being selected on the basis of results of a 13-week subchronic toxicity study. Body weight gains were slightly depressed in the 125 ppm group of both sexes. While not statistically significant in females, final survival rates at week 111 in the 125 ppm group of both sexes were higher than those in the control group, suggesting an ability of 5-FU to prolong the lifespan. Histopathologically, a decreased incidence of islet cell adenomas in males and increased incidences of pituitary gland adenomas and pheochromocytomas in females were observed in the 62 ppm group without dose dependence. There was no significant induction of any other neoplastic or non-neoplastic lesions. These results indicate a lack of carcinogenicity of 5-FU under the present experimental conditions using rats.
Adenoma↗
Fatal erythroderma (suspected graft-versus-host disease) after cholecystectomy. Retrospective analysis.
Fatal postoperative erythroderma (POE) developed in a 52-year-old woman with gallstones who underwent elective cholecystectomy. During surgery, she was transfused with 3 units of unirradiated packed red cells stored in the liquid state for at least 4 days after collection. The POE is believed to have been the result of transfusion-associated graft-versus-host disease (TA-GVHD). The diagnosis of GVHD was based upon the characteristic clinical picture and retrospective HLA typing. The implicated donor was homozygous for an HLA haplotype that appeared to be shared with the recipient: A24-CBL-Bw52-DR2-DRw52-DQw1, the most common haplotype in the Japanese population. This case raises the possibility that a transfusion of relatively fresh blood from a donor who has no HLA antigens incompatible with the recipient may result in GVHD in patients with no apparent immunoincompetence who are undergoing relatively minor surgery with no chemotherapy or radiation therapy.
Blood Transfusion↗
The critical role of blood from HLA-homozygous donors in fatal transfusion-associated graft-versus-host disease in immunocompetent patients.
Fatal transfusion-associated graft-versus-host disease developed in a 69-year-old woman with colon cancer who underwent elective hemicolectomy. During the perioperative period, she was transfused with 4 units of nonirradiated fresh whole blood less than 6 hours after the blood was donated by family members. She was immunocompetent and was not treated with any immunosuppressive agents such as corticosteroids, chemotherapy, or irradiation therapy. The implicated donor was thought to be her daughter, who was homozygous for an HLA haplotype that was shared with the recipient: A24, Bw52, CBL, DR2. This is the most common haplotype in the Japanese population. This case and others in the Japanese literature indicate that the transfusion of fresh, nonirradiated blood that contains immunocompetent lymphocytes and peripheral hematopoietic precursor cells from HLA-homozygous donors can be lethal to the recipient.
Aged↗
Immunohistochemical and ultrastructural studies of 2,6-dimethylaniline-induced nasal proliferative lesions in a rat two-stage nasal carcinogenesis model initiated with N-bis(2-hydroxypropyl)nitrosamine.
Proliferative lesions induced by 2,6-dimethylaniline (DMA) in a two-stage rat nasal carcinogenesis model were immunohistochemically and ultrastructurally investigated. Male F344 rats received diet containing 3,000 ppm DMA for 52 weeks after initiation with a single subcutaneous injection of 2400 mg/kg of N-bis(2-hydroxypropyl)nitrosamine (DHPN). Histopathologically, proliferation of Bowman's glands, glandular hyperplasias, dysplastic foci, adenomas, and carcinomas were observed in treated rats. These nasal lesions mostly arose in the olfactory mucosa of the nasal cavity. Immunohistochemically, they were positive for cytokeratin and/or collagen type IV antibodies. Ultrastructurally, intracytoplasmic dense secretory granules (200-850 nm in diameter), identical to those in normal Bowman's glands, were observed in all the lesions, providing further support from an origin from these glands. Based on their cellular characterization, growth pattern and/or proliferative activity, two morphological continua were evident, one from dysplastic foci to carcinomas and the other from proliferation of Bowman's glands to glandular hyperplasias and adenomas. These results suggest that dysplastic foci arise from Bowman's glands and progress to carcinomas, while proliferation of Bowman's glands result in glandular hyperplasias and adenomas.
Adenoma↗
Induction of pancreatic islet cell tumors in rats by repeated intravenous administration of 4-hydroxyaminoquinoline 1-oxide.
The inducibility of pancreatic islet cell tumors by administration of 4-hydroxyaminoquinoline 1-oxide (4HAQO) was investigated in male 6-week-old Sprague-Dawley rats. Rats were given 4HAQO intravenously at a weekly dose of 5 mg/kg 4 times (group 1) or a single dose of 10 mg/kg (group 2). Control rats received the vehicle alone (group 3). Fifty-six weeks after the first 4HAQO administration, all surviving animals were killed and the pancreas was examined histopathologically, immunohistochemically and ultrastructurally. The incidences and multiplicities of islet cell tumors in groups 1, 2, and 3 were 52.3% (p < 0.05 vs group 2, p < 0.01 vs group 3), 19.2% and 0%, and 0.70/animal (p < 0.05 vs group 2, p < 0.01 vs group 3), 0.23 and 0, respectively. Islet cell carcinomas were induced only in group 1, accounting for 6/44 (26%) tumors. Islet cell hyperplasias were found in 61.4% (p < 0.05 vs group 3), 42.3% and 10.0% of groups 1, 2, and 3, with multiplicities of 0.95 (p < 0.05 vs groups 2 and 3), 0.54 and 0.20, respectively. As compared with normal islets from control subjects, islet cell tumors showed an increase in the number of insulin positive cells associated with cytological features indicative of enhanced insulin synthesis and secretion, and a decrease in the number of glucagon positive cells without ultrastructural signs of modified secretory activity. Thus our results indicate that repeated intravenous administration of 4HAQO to rats is useful for the induction of islet cell tumors at high incidence.
4-Hydroxyaminoquinoline-1-oxide↗
Dose-dependent induction of glandular stomach preneoplastic and neoplastic lesions in male F344 rats treated with catechol chronically.
The dose-dependence of catechol glandular stomach carcinogenesis was investigated in male F344 rats. Groups of 30 male animals were fed catechol at dietary levels of 0 (control). 0.1, 0.2, 0.4, and 0.8% for up to 104 weeks. Five rats of each group were killed at 34 weeks and the remaining animals were sacrificed at the termination, all undergoing histopathological examination. Moderate retardation of body weight increase was observed in the 0.8% group. but no adverse effects were found in terms of survival. Submucosal hyperplasias and adenomas of the pyloric glands developed in the 0.4 and 0.8% groups, only very minor changes being noted in the 0.1 and 0.2% groups at week 34. Incidences of adenocarcinoma development in the pylorus were 4% and 8% in 0.4% and 0.8% groups, respectively, and 0 in the 0.1% and 0.2% groups, at the termination. Adenomas and submucosal hyperplasias were found in nearly all animals fed 0.2% catechol or more, the incidences of those in 0.1% group being 0% and 56%, respectively. Serum gastrin levels were significantly increased in the 0.2, 0.4, and 0.8% groups at 34 weeks, and in all treated groups at the termination, at extents comparable with the induction of proliferative lesions in the pylorus. The results thus demonstrated that dietary levels of 0.4% and 0.8% catechol long-term induce adenocarcinomas in the pyloric glands, while 0.1 and 0.2% cause benign proliferative lesions, all accompanied by increase in serum gastrin levels. As a no-effect level could not be decided in the present study, further investigation of lower doses is needed to determine whether a threshold exists.
Adenocarcinoma↗
Toxic effects of benzyl and allyl isothiocyanates and benzyl-isoform specific metabolites in the urinary bladder after a single intravesical application to rats.
Allyl isothiocyanate (AITC) is known to be weakly carcinogenic, whereas benzyl isothiocyanate (BITC) has been suggested to exert carcinogenicity toward the rat urinary bladder. To elucidate direct toxic effects of isothiocyanates (ITCs), BITC, AITC, or BITC-metabolites conjugated either with glutathione, cysteinylglycine, cysteine, or mercapturic acid were intravesically instilled into female F344 rats. Exposure to AITC and BITC at 2.8 mg/kg body weight, and the same mol quantity (37 micromol/kg) of BITC-metabolites was for 2 h. Nineteen hours thereafter, the animals were intravenously administered 5-bromo-2'-deoxyuridine (BrdU) and killed 1 h later. BITC caused more profound toxic damage than AITC. Among the BITC-metabolites, cytotoxicity was evident with intermediate glutathione or cysteinylglycine conjugates, whereas the mercapturic acid, considered to be the major final urinary metabolite, exerted little effects. BrdU labeling was essentially dependent on the degree of cytotoxic potential of each compound. Considering the previous study results demonstrating the generation of free BITC from metabolites in urine, the present results support the idea that cytotoxic activity of orally administered ITCs is derived from free forms cleaved from conjugated metabolite(s) in urine.
Acetylcysteine↗
Pertussis toxin-induced redistribution of cortical actomyosin and inhibition of phagocytosis in rat Kupffer cells.
The mechanism of phagocytosis by Kupffer cells has been shown to be related to the Ca(2+)-calmodulin and the actomyosin systems. However the role of the transmembrane signal transmitter, G-protein, is still unknown. In this study, a quantitative evaluation of phagocytosis by Kupffer cells of rats in culture and the effects of pertussis toxin, a G-protein inhibitor, on the phagocytic function and morphology of Kupffer cells were investigated. Pertussis toxin inhibited phagocytosis of Kupffer cells with dysfunction of the actomyosin system. The inhibitory effects of pertussis toxin suggest that G-protein may be involved in the mechanism of transmembrane signalling in phagocytosis by Kupffer cells.
Actins↗