Biomedical subjects

S Tamano

Publications and source records attributed to S Tamano.

103 records · Page 6Linked to original sources

PubMed1984

Three-dimensional observations by scanning electron microscopy on the blood supply and organization of vasculature during hepatocarcinogenesis in rats.

Three-dimensional vascular changes in rats during hepatocarcinogenesis were studied by stereoscopic and scanning electron microscopic observation of vascular casts of sinusoids by injecting resin from hepatic artery (red color) and portal vein (blue color). Neoplastic lesions were synchronously induced by injection of diethylnitrosamine (DENA) followed by feeding of 2-acetylaminofluorene (2-AAF) plus partial hepatectomy, then periodically killed for examination. At 6 weeks after DENA injection sinusoids of hyperplastic foci (HF) were filled with blue resin similar to surrounding tissue, then at 8 weeks some HF and hyperplastic nodules (HN) took up red resin leaving surrounding sinusoids blue. At 12 to 18 weeks, red HN became more discrete with obvious compression of surroundings but decreased their number whereas blue HN were not. Red HN had incomplete anastomosing sinusoids giving a coral-like appearance. Spongy or cystic areas contained little or no resin, suggesting ischemic condition. Hepatocellular carcinomas (HCC) at 40 weeks took exclusively arterial red resin forming irregularly shaped anastomosing sinusoids. These findings indicate that acquisition of arterial blood supply by HF may relate to their further development to persistent HN and HCC.

2-Acetylaminofluorene↗

PubMed1984

[Effect of diuretic, azosemide (SK-110), in combination with antibiotic, cephaloridine, on kidney].

This study was performed to compare the acute-renal toxicity of azosemide (SK-110) or furosemide (FM) treatment in combination with cephaloridine (CER). 1) Initially, the acute-renal toxicity of CER was studied after a subcutaneous administration at dose levels of 500, 1000, 1500 and 2000 mg/kg. The values of BUN, creatinine and relative kidney weights were increased in rats given CER at dose levels above 1500 mg/kg. consequently, it was considered that the threshold of CER with regard to acute-renal toxicity was 1000 mg/kg. 2) Secondarily, the acute-renal toxicity of SK-110 or FM were studied after oral administration of 40, 80, 160 or 320 mg/kg doses alone or in combination with CER. Acute-renal toxicity was evident in the 320 mg/kg-treated rats after both SK-110 and FM alone, as revealed by analysis of a number of parameters, i.e., BUN, serum creatinine, urine sediment and composition and pathological data composing both kidney weights and studies at the microscope level. However, the increase of BUN and relative kidney weights values, elevated numbers of epithelial cells in the urine and necrosis observed in the uriniferous-tubular epithelium on histopathological examination of kidneys were noted in rats given at dose levels of only 80 mg/kg with SK-110 + CER, whereas they were seen in animals treated with FM even at the lowest applied dose of 40 mg/kg in combination with CER. In conclusion, this study showed that the minimum dose of SK-110 or FM in combination with CER which causes acute-renal toxicity were, respectively, 80 mg/kg or less than 40 mg/kg.

Administration, Oral↗

PubMed1984

[Effect of azosemide (SK-110) and its metabolites on mouse liver].

The effect of azosemide (SK-110), and its metabolites, 5-(2'-amino-4'-chloro-5'-sulfamoylphenyl)-tetrazole (M-1), 2-thiophenecarboxylic acid (TC), on mouse liver was investigated using biochemical and pathological parameters as indices of hepatotoxicity. The effects were compared with that of furosemide (FM) administration. A single dose of each compound was administered orally, or intraperitoneally, while multiple oral dosing was carried out once daily for a week. The results are summarized as follows: 1) SK-110 did not produce hepatotoxicity even after a single p.o. dose as high as 5000 mg/kg, a single i.p. dose of 400 mg/kg, or multiple p.o. doses of 700 mg/kg/day. 2) M-1 also did not produce hepatotoxicity even after a single p.o. dose of 4000 mg/kg or multiple p.o. doses of 550 mg/kg/day. TC did not exert hepatotoxicity after a single i.p. dose of 150 mg/kg or multiple p.o. doses of 250 mg/kg/day, but did produce hepatotoxicity after a single p.o. dose of more than 1000 mg/kg. However, it was presumed that, in vivo, TC formed as a metabolite of administered SK-110 would hardly produce hepatotoxicity. 3) FM produced hepatotoxicity after a single p.o. dose of more than 800 mg/kg, or a single i.p. dose of more than 200 mg/kg, but not after multiple p.o. doses of 700 mg/kg/day. Based on these findings, it was concluded that, in contrast to FM, SK-110 had no hepatotoxic effect on the mouse liver.

Administration, Oral↗

PubMed1984

Promotion of 2-(ethylnitrosamino)ethanol-induced renal carcinogenesis in rats by nephrotoxic compounds: positive responses with folic acid, basic lead acetate, and N-(3,5-dichlorophenyl)succinimide but not with 2,3-dibromo-1-propanol phosphate.

The promoting effects of nephrotoxic chemicals, folic acid (FA), N-(3,5-dichlorophenyl)succinimide (NDPS), 2,3-dibromo-1-propanol phosphate (Tris-BP), and basic lead acetate (LAB), on 2-(ethylnitrosamino)ethanol (EHEN)-induced renal carcinogenesis were examined in F344 rats. The rats were treated with 0.1% EHEN in their drinking water for 1 week and then given one of the nephrotoxic chemicals for 35 weeks. FA was injected sc once a week at a dose of 300 mg/kg for the first 8 weeks and thereafter at 100 mg/kg. NDPS, Tris-BP, and LAB were mixed in the diet at concentrations of 0.5, 0.01, and 0.1%, respectively. At week 3 the right kidney was removed to enhance renal neoplasia. Renal cell tumor incidence was significantly increased by both FA and LAB and was slightly increased by NDPS, whereas Tris-BP had no effect. The data show that FA, LAB, and NDPS are promoters of EHEN-induced renal carcinogenesis.

Animals↗

PubMed1983

Dose and sex dependent effects of 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene and DL-ethionine in induction of gamma-glutamyl transpeptidase-positive liver cell foci in rats.

The dose-dependent and sex-related effects of 3 hepatocarcinogens were investigated by measuring the number and area of gamma-glutamyl transpeptidase (gamma-GT) positive foci appearing in the liver. For this, three different doses of 2-acetylaminofluorene (2-AAF), 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) and DL-ethionine (ethionine), respectively, were given to F344 rats of both sexes for 6 weeks after a single injection of diethylnitrosamine (DEN). The inductions of gamma-GT positive foci by 2-AAF and 3'-Me-DAB were clearly dose-dependent, but with 2-AAF this was clearer in males than females. Ethionine had less clear dose-dependent effects in both males and females. Under these conditions, the minimal effective doses of 2-AAF, 3'-Me-DAB and ethionine, respectively, were 0.0008%, 0.0024% and 0.05% in males and 0.004%, 0.012% and 0.05% in females. The results indicate that these 3 carcinogens had clear dose-dependent effects in the induction of gamma-GT positive foci when given for a short period in the promotive stage and that male rats were more susceptible than females to 2-AAF.

2-Acetylaminofluorene↗

PubMed1983

Sequential observations on the appearance of neoplastic lesions in the liver and kidney after treatment with N-ethyl-N-hydroxyethylnitrosamine followed by partial hepatectomy and unilateral nephrectomy.

Sequential observations were carried out on the induction of preneoplastic lesions in the liver and the kidney. Rats were initially given N-ethyl-N-hydroxyethylnitrosamine (EHEN) in their drinking water (0.1%) for 3 days (Group 1), 1 week (Group 2) or 2 weeks (Group 3) or tap water (Group 4). Rats in Groups 1-3 were subjected to partial hepatectomy and unilateral nephrectomy (right side) 2 weeks after the end of EHEN treatment. Rats from these groups were killed in week 10, 20, 30 and 40 of the experiment. In the liver, the effect of EHEN in the induction of gamma-glutamyltranspeptidase (gamma-GT) positive foci and hyperplastic nodules (HN) was clearly dependent on the length of treatment. The preneoplastic lesions increased with the lapse of observation time. Changes measured as number of gamma-GT positive foci were 10-40 times greater than those measured as HN, especially among the small size range. Values for changes in Group 1 given 0.1% EHEN for 3 days were very low, indicating that this dose is close to the threshold. Two rats with hepatocellular carcinoma in Group 3 given EHEN for 2 weeks survived until week 40. In the kidney, tubular epithelial proliferations composed of cells with slightly basophilic cytoplasm and slightly atypical nuclei were tentatively named atypical cell foci (ACF). EHEN induced ACF, renal cell adenomas and renal cell carcinomas. The increase in the induction of ACF was dependent on the length of observation period but not on the length of treatment. Even though control rats (not treated with EHEN) also had ACF, their quantitative values were far less than the groups given EHEN and killed at week 40, indicating that a large number of ACF were induced by EHEN. Therefore, EHEN is good for experimental induction of preneoplastic lesions in the liver and kidney of rats. The experimental schedule for Groups 1 and 2 could be used as a shortterm screening test for promoters and the schedule for Group 3 as an assay for inhibitors.

Animals↗

PubMed1983

Inhibitory effect of butylated hydroxyanisole and ethoxyquin on the induction of neoplastic lesions in rat liver after an initial treatment with N-ethyl-N-hydroxyethylnitrosamine.

The effect of butylated hydroxyanisole (BHA) and ethoxyquin (EQ) on hepatocarcinogenesis initiated with N-ethyl-N-hydroxyethylnitrosamine in rats was investigated. The results clearly demonstrated that BHA and EQ inhibited the development of gamma-glutamyltranspeptidase - positive foci, hyperplastic nodules and hepatocellular carcinomas in the rat system employed.

Animals↗

PubMed1982

Organ-specific promoting effects of phenobarbital sodium and sodium saccharin in the induction of liver and urinary bladder tumors in male F344 rats.

Studied were conducted to determine whether initial treatment with N-2-fluorenylacetamide (2-FAA) or N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) followed by treatment with either phenobarbital sodium (PB) or sodium saccharin (SS) induced or enhanced liver and/or bladder tumorigenesis. Male inbred F344 rats were given 0.05% PB and 5.0% SS in the diet for 32 weeks after 4-week administration of 0.02% 2-FAA treatment and induced hyperplastic liver nodules after BBN treatment. The SS significantly enhanced induction of bladder hyperplasias, but not papilloma after BBN treatment, and induced bladder hyperplasias after 2-FAA treatment. However, PB had no effect on the bladder and SS had no effect on the liver after either 2-FAA or BBN treatment. The data indicate that although 2-FAA and BBN have tumor-initiating effects in the liver and urinary bladder, the tumor-promoting effects of PB and SS are organ-specific. The tumor-promoting effect of PB for the liver is relatively greater than that of SS for the urinary bladder.

2-Acetylaminofluorene↗

PubMed1981

Induction of gamma-glutamyl transpeptidase positive foci in rat liver by pyrolysis products of amino acids.

The activities of pyrolysis products for initiating or promoting preneoplastic lesions were tested. In experimental series I, N-2-fluorenylacetamide (2-FAA) was used as an initiator or a promoter and 3-amino-1,4-dimethyl-5H-pyrido-[4, 3-b] indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido [4, 3-b] indole (Try-P-2), 2-amino-6-methyldipyrido [1,2-a:3', 2'-d] imidazole (Glu-P-1) or 2-amino-dipyrido [1, 2-a:3', 2'] imidazole (Glu-P-2) was administered at a fixed dose and for the same period in the initiation stage or the promotion stage. Animals were subjected to partial hepatectomy or treated with carbon tetrachloride (CCl4) to increase the induction of gamma-glutamyl transpeptidase (gamma-GT) positive foci. Trp-P-1 and Glu-P-2 administered in either the initiation or promotion stage significantly increased the induction of gamma-GT positive foci (p less than 0.001). Glu-P-1 increased the induction of gamma-GT positive foci (P less than 0.001) when administered in the initiation stage but it was not effective when administered during the promotion stage. In experimental series II, animals were given a single dose of these chemicals at one of three different dose levels with partial hepatectomy and then were fed with 2-FAA and given a single dose of CCl4. Trp-P-1, Glu-P-1 and Glu-P-2 caused dose-dependent inductions of gamma-GT positive foci.

2-Acetylaminofluorene↗

PubMedDate not supplied

Effects of pesticide mixtures at the acceptable daily intake levels on rat carcinogenesis.

Possible modifying effects of pesticide mixtures on tumorigenesis were investigated with medium-term carcinogenesis protocols for rapid detection of carcinogenic agents using male F344 rats. In the 8-wk liver model, administration of 20 pesticides (19 organophosphorus compounds and one organochlorine), added to the diet each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of these 20 pesticides at 100 times the ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 wk, mixtures of 40 pesticides (high production examples) or 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not modulate carcinogenesis in any organ initiated by five known potent carcinogens in combination. These results thus provide direct support for the safety factor (usually 100) approach using ADI values for the quantitative risk evaluation of pesticides.

Administration, Oral↗

PubMedDate not supplied

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↗

PubMedDate not supplied

Immunohistochemical detection of 8-hydroxy-2'-deoxyguanosine in paraffin-embedded sections of rat liver after carbon tetrachloride treatment.

To test the applicability of an anti-8-hydroxy-2'-deoxyguanosine (8-OH-dG) antibody for immunohistochemistry using paraffin-embedded sections, carbon tetrachloride (CCl4)-induced rat liver injury was evaluated. Male rats were given a single dose of CCl4 and killed at 6 hr, 12 hr, 1, 2, 3, and 7 days thereafter. Severe centrilobular necrosis was evident at 1 day. At 2 days, moderate mononuclear cell infiltration was present in centrilobular necrotic regions. Infiltrating mononuclear cells, surrounding sinusoidal endothelial cells and hepatocytes were stained with anti-8-OH-dG antibody at 2 and 3 days. Formation of 8-OH-dG in DNA and 8-oxo-dGTPase mRNA expression were also increased at these time points, the amounts of malondialdehyde and 4-hydroxy-2-nonenal showed 2 peaks at 6 hr and 3 days. The findings suggest that the main contributory factor in the massive hepatic necrosis was increased lipid peroxidation, rather than excessive formation of 8-OH-dG, and that the observed increase in the latter was largely due to infiltrating mononuclear cells. The agreement between biochemical data and the results for immunohistochemical analysis confirms that the anti-8-OH-dG antibody is applicable for detection of cells targeted by free radicals in paraffin-embedded sections and also for investigation of the mechanisms of oxidative damage-related disease, including carcinogenesis.

8-Hydroxy-2'-Deoxyguanosine↗

PubMedDate not supplied

Marriage of a medium-term liver model to surrogate markers--a practical approach for risk and benefit assessment.

The need for a reliable medium-term alternative to traditional long-term rodent test protocols for carcinogen risk assessment is pressing given the immense variety of compounds being developed for introduction into the human environment. The established lack of a complete correlation between mutagenicity and carcinogenicity means that recourse must be made to an in vivo model. Optimally, this model should be able to detect not only complete carcinogenic or promoting potential but also any ability to inhibit neoplasia. In order to be effective, it must take into account the available detailed knowledge on mechanisms of action of carcinogens and modulating agents. The Ito model, for which a uniquely comprehensive set of background data has already been accumulated, has a solid scientific basis; this model utilizes quantitative data for glutathione S transferase-positive foci as the preneoplasia-based surrogate end point (PSE). A very practical candidate for routine application, its predictive power, its flexibility, and its capacity to incorporate a range of mechanism-based surrogate end points (MSEs) provide a powerful tool for attainment of the twin goals of detecting carcinogenic agents and identifying promising chemopreventors.

Animals↗