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Biomedical subjects

N Ito

Publications and source records attributed to N Ito.

At least 505 records · Page 28Linked to original sources
PubMed1989

Hepatotoxicity of agents that enhance formation of focal hepatocellular proliferative lesions (putative preneoplastic foci) in a rapid rat liver bioassay.

The histopathology of hepatic toxicity for 58 chemicals previously tested in a rapid rat liver bioassay for demonstrating potential hepatocellular carcinogens and/or tumor promoters was reviewed. Rats received the test diet for 1 week prior to partial hepatectomy and for an additional 5 weeks thereafter at doses near the estimated maximally tolerated dose. These rats served as controls for others receiving initiation by N-nitrosodiethylamine (DEN) and the test diets. Twenty-two of these chemicals were previously found to enhance the formation of glutathione S-transferase, placental form (GST-P)-positive putative preneoplastic hepatocellular foci (promoters) following DEN initiation in this rapid bioassay, whereas 36 chemicals did not. Of the agents that promoted GST-P-positive foci, 14/22 (63.6%) produced toxic hepatocyte lesions while only 4/36 (11.1%) of the nonpromoters did so at the doses used. Biliary toxicity was found for 7/22 (31.8%) of the promoters and 6/36 (16.7%) of the nonpromoters. Only 2/13 (15%) chemicals that inhibited GST-P-positive foci produced hepatic toxicity. Thus, agents that were presumed hepatic tumor promoters characteristically were hepatotoxins while nonpromoters of carcinogenesis were not hepatotoxins in this rapid rat liver bioassay.

Animals↗
PubMed1989

Lack of carcinogenicity of magnesium chloride in a long-term feeding study in B6C3F1 mice.

Groups of 50 male and 50 female B6C3F1 mice were given magnesium chloride (MgCl2.6H2O) at dose levels of 0 (control), 0.5 and 2% in the diet for 96 wk, after which all animals received the control diet for 8 wk and were then necropsied. In females of the high-dose group a decrease in body weight was observed. However, survival rates did not differ between the treatment and control groups for males or females. Furthermore, clinical signs and urinary, haematological or serum clinical chemistry parameters showed no treatment-related effects. On histological examination, tumours were mainly found in the skin/subcutis, liver and lymphatic system. However, with the exception of a significant decrease in the incidence of liver tumours among males of the high-dose group, no differences were noted in the tumour incidence between the treated and control animals. Thus, the study described here clearly shows a lack of carcinogenicity of MgCl2.6H2O given to B6C3F1 mice in the diet.

Animals↗
PubMed1989

Long-term feeding study of N,N'-diphenyl-p-phenylenediamine in F344 rats.

Groups of 50 F344 rats of each sex were fed a diet containing 0.5 or 2% of N,N'-diphenyl-p-phenylenediamine (DPPD) for 104 weeks and were killed 8 weeks after the cessation of DPPD administration. DPPD-treated rats of both sexes showed a dose-dependent reduction in body weight gain, but no lower survival rate, when compared with untreated control rats. Blood and urine analysis showed no remarkable changes due to the treatment. Calcium deposition in the kidney of males was the only significant histological change relating to the treatment. Tumors were found in many organs of all groups, but a significant increase of tumor induction in DPPD-treated groups was not observed.

Administration, Oral↗
PubMed1989

DNA-adduct formation in the forestomach of rats treated with 3-tert-butyl-4-hydroxyanisole and its metabolites as assessed by an enzymatic 32P-postlabeling method.

Formation of DNA-adducts by 3-BHA or its metabolites, i.e., tert-butyl-1,4-benzoquinone (TBQ) and 5-methoxy-3-tert-butyl-1,2-benzoquinone (3-TBOQ), as well as DNA-adduct formation by 4-nitroquinoline-N-oxide (4NQO), in rat forestomach were examined by an enzymatic 32P-postlabeling assay. Four DNA-adducts were clearly detected in the forestomach after treatment of rats with 4NQO. The sensitivity was 1.9 certain adducts per 10(8) normal nucleotides. On the contrary, no DNA adducts were detected in the forestomach of rats given either a single or repeated oral administration (5 days) of 3-BHA, TBQ or 3-TBOQ. The analyses were carried out under conditions which could detect the DNA-adducts produced by reaction of TBQ with calf thymus DNA in vitro. The results suggest that formation of aromatic adducts in vivo by 3-BHA, TBQ or 3-TBOQ in the rat forestomach-DNA is not evident or at least below the detection limits of the current bioassay.

4-Nitroquinoline-1-oxide↗
PubMed1989

Modification by sodium L-ascorbate, butylated hydroxytoluene, phenobarbital and pepleomycin of lesion development in a wide-spectrum initiation rat model.

Rats were treated for 1 week each with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), 0.2% N-bis(2-hydroxypropyl)-nitrosamine (DHPN) and 0.2% N-ethyl-N-hydroxyethylnitrosamine (EHEN) in the drinking water, and then administered diet containing 5% sodium L-ascorbate (Na-AsA), 1% butylated hydroxytoluene (BHT) or 0.05% phenobarbital (PB), or weekly intraperitoneal injections of 2 mg of pepleomycin per kg body weight until week 36. Histopathological examination revealed that all exerted significant modulation effects on tumor development in the various target organs. Na-AsA was found to inhibit liver but promote renal pelvis and bladder carcinogenesis. BHT similarly decreased liver and enhanced bladder lesion development. PB, in contrast promoted hepatocarcinogenesis. However both PB and BHT were associated with increased incidences of adenomas and adenocarcinomas of the thyroid. Thus the wide-spectrum initiation model allowed confirmation of site-specific modification potential and in addition demonstrated potentiation of kidney and bladder carcinogenesis promotion by pepleomycin.

Animals↗
PubMed1989

Antioxidants--carcinogenic and chemopreventive properties.

Synthetic and naturally occurring antioxidants have a wide variety of biological actions in rodents in addition to their primary antioxidant activity. Some of the included biological effects are of direct interest in relation to studies of carcinogenicity and/or modulation of carcinogenesis. Since the synthetic antioxidant BHA was first found to exert carcinogenic potential in rat and hamster forestomach epithelium, many other synthetic and naturally occurring antioxidants have been examined for their ability to induce proliferative activity in the alimentary canal. These studies have revealed that caffeic acid and sesamol are also tumorigenic for rat forestomach epithelium, whereas catechol and p-methylcatechol induce neoplasia in rat glandular stomach epithelium. Although the proliferative response is very rapid, with inflammation and ulceration, it takes a very long time before carcinomas develop. The proliferative lesions in the forestomach induced by BHA or caffeic acid are largely reversible, in contrast to those induced by genotoxic carcinogens, which generally persist and develop into cancer. Therefore, chronic irritation is considered to be responsible for the induction of stomach cancer by antioxidants. Butylated hydroxyanisole can undergo oxidative metabolism in vitro, and some of the metabolites formed have the potential for binding to proteins. Neither BHA nor its metabolites binds to DNA in vivo, but protein binding in the forestomach was greater than 10 times higher than that in the glandular stomach. It is thus conceivable that BHA is oxidatively metabolized in the forestomach epithelium (possibly entering into redox cycling), and reactive metabolites including semiquinone radicals or active oxygen species are responsible for the carcinogenesis by a mechanism involving binding to macromolecules. Many antioxidants have been shown to modify carcinogenesis, and as a rule, they inhibit the initiation stage by reducing the interaction between carcinogen and DNA. However, both promotion and inhibition have been reported for second-stage carcinogenesis, depending on the organ site, species of animal, or initiating carcinogen. They can also block reaction of amine and nitrite to form nitrosamines or reduce TPA promotion of skin carcinogenesis. Generally high doses of antioxidants are required for carcinoma induction or modification of chemical carcinogenesis. The significance of the reported tumorigenicity and strong promoting activity of antioxidants for forestomach epithelium of animals to the development of human cancer appears limited mainly because humans do not have a forestomach. The carcinogenic and strong promoting activities of catechol and its structurally related compounds on rat glandular stomach epithelium are of greater concern because this tissue is directly analogous to human gastric epithelium.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Transient induction of single GST-P positive hepatocytes by DEN.

The single cells positive for placental glutathione S-transferase (GST-P), detectable in livers of rats soon after treatment with hepatocarcinogens, are possible 'initiated cells', the hypothesis tested in the present series of experiments. No low dose threshold was observed in male Sprague-Dawley rats at different single doses of diethylnitrosamine (DEN) although a plateau was reached between 160 and 200 mg/kg body weight. At the latter single dose approximately 12,400 positive cells/cm3 were observed immunohistochemically in rat livers after one week, the numbers then decreasing to week 8 and thereafter rising again. In the early stages single cells predominated but with time a gradual increase in mini-foci and larger lesions became evident. Application of selection pressure (feeding of diet containing 0.02% 2-AAF plus partial hepatectomy) to rats 2-24 weeks after single DEN-treatment resulted in the formation of large foci positive for GST-P, especially in the early stages, the growth response being less pronounced with time. The number of foci, on the other hand, was correlated with the number of single cells/mini-foci detected in hepatectomy tissue of the same individuals. These results suggest that the early GST-P positive populations could be the precursor for preneoplastic foci and nodules.

Animals↗
PubMed1989

Antagonistic effect of diethylmaleate on the promotion of forestomach carcinogenesis by butylated hydroxyanisole (BHA) in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine.

The effects of diethylmaleate (DEM), previously demonstrated to inhibit butylated hydroxyanisole (BHA)-induced forestomach hyperplasia, on BHA promotion of forestomach carcinogenesis in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were examined. Groups of male 6-week-old F344 animals were given a single i.g. administration of 150 mg/kg body weight MNNG and starting 1 week later administered powdered diet containing 1% BHA plus 0.2% DEM, 1% BHA, 0.2% DEM or basal diet alone for 51 weeks. Further groups of rats were treated with 1% BHA plus 0.2% DEM, 1% BHA, 0.2% DEM or basal diet alone without MNNG pretreatment. Histopathological assessment of lesions at week 52 revealed enhancement of MNNG-initiated papilloma (100 versus 50%) and squamous cell carcinoma (100 versus 0%) development by BHA as compared to controls. Additional treatment with DEM, however, significantly reduced the relative incidences of carcinoma in situ (0 versus 35.7%) and squamous cell carcinoma (35.7 versus 100%), as well as BHA-induced forestomach hyperplasia with or without prior MNNG treatment. The results thus clearly demonstrate that DEM acts as a potent antagonist to BHA-promotion of rat forestomach carcinogenesis.

Animals↗
PubMed1989

Modulation of diethylnitrosamine-initiated placental glutathione S-transferase positive preneoplastic and neoplastic lesions by clofibrate, a hepatic peroxisome proliferator.

The effect of clofibrate (CF) on proliferation of diethylnitrosamine (DEN)-initiated glutathione S-transferase placental form (GST-P)-positive preneoplastic and neoplastic lesions as studied in male F344 rats. Animals were given a single i.p. injection of 200 mg/kg body weight of DEN, and then from 2 weeks later were given a diet containing 0.3% CF (group 1), or no supplement (group 2) until week 64. Group 3 received an injection of 0.9% NaCl instead of DEN and then a diet containing 0.3% CF, like group 1. Animals in all groups were subjected to partial hepatectomy at week 3 and killed at weeks 8, 20, 32, 49 or 64. The results showed that development of GST-P-positive lesions was significantly less in group 1 than in group 2 from week 8 (P less than 0.05). However, in group 1, morphologically distinguishable GST-P-negative preneoplastic lesions increased from week 20 (P less than 0.05), and the total number of GST-P-positive and -negative lesions was significantly greater than that in group 2 from week 32 (P less than 0.05). The induction of hepatocellular carcinoma (HCC) was greater in group 1 than in group 2 from week 49. All the HCCs induced in group 2 were GST-P-positive, whereas 38.9% (7/18) of those in group 1 were GST-P-negative. In group 3, only a few GST-P-positive and/or -negative preneoplastic lesions developed by week 64. These results suggest that CF has tumor-promoting activity, and that GST-P-positive cells induced by DEN changed to GST-P-negative cells on subsequent treatment with CF.

Animals↗
PubMed1989

Modifying effects of simultaneous treatment with butylated hydroxyanisole (BHA) on rat tumor induction by 3,2'-dimethyl-4-aminobiphenyl, 2,2'-dihydroxy-di-n-propylnitrosamine and N-methylnitrosourea.

The modifying effects of concurrent treatment with high or low doses of butylated hydroxyanisole (BHA) on wide-spectrum carcinogen-induced carcinogenesis were studied in male F344 rats. Groups of 20 animals were treated with 2 or 0.04% BHA for 24 weeks. Starting 2 weeks after the commencement of BHA treatment, they were given s.c. injection of 50 mg/kg body weight 3,2'-dimethyl-4-aminobiphenyl (DMAB) once a week, i.g. administrations of 200 mg/kg body weight 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) once every 2 weeks, or i.p. injection of 15 mg/kg body weight N-methylnitrosourea (MNU) once every 2 weeks for 22 weeks. Further groups of rats were treated with DMAB, DHPN, MNU, or 2 or 0.04% BHA alone. All surviving animals were killed 24 weeks after the beginning of the experiment and the target organs examined histopathologically. The BHA treatment dose-dependently decreased the incidence of DMAB-induced liver preneoplastic lesions but was associated with significant tumor induction in the forestomach (papillomas, 40%, P less than 0.01) and urinary bladder (papillomas, 53%, P less than 0.001; carcinomas, 80%, P less than 0.001), where no lesions were observed in the group given only DMAB. Concurrent administration of 2% BHA also significantly inhibited the development of alveolar hyperplasia (P less than 0.001) of the lung in DHPN-treated animals, while enhancing induction of forestomach papillomas (P less than 0.05) and simple hyperplasia in the urinary bladder. Neither MNU nor 2% BHA alone induced forestomach carcinoma or papillary or nodular hyperplasia (PN hyperplasia) in the urinary bladder. However, these lesions were observed in 100% (P less than 0.001) and 55% (P less than 0.001) of animals respectively, receiving the two compounds in combination. These results demonstrated that concurrent treatment with BHA not only inhibits but can also strongly enhance carcinogenesis depending on the organ, irrespective of whether the carcinogens act directly or require metabolism. The finding that BHA potently modified carcinogenesis at 0.04% in diet, 1/50 of the carcinogenic dose, suggests that actual dietary levels close to the human situation might play a significant role in tumor development in man.

Aminobiphenyl Compounds↗
PubMed1989

Placental form of glutathione S-transferase in normal and diseased human uterine cervical mucosa.

Expression of the human placental form of glutathione S-transferase (GST-pi), an enzyme proposed as a marker for human and experimental neoplasia, was immunohistochemically evaluated in 51 samples of 'normal' and diseased adult human uterine cervix. Five fetal uteri were also studied. GST-pi positivity was detected in 54, 92, 95 and 83% of the 'normal', non-neoplastic, cervical intra-epithelial neoplasia (CIN) and cancer cases respectively. All five fetal uteri and the positive 'normal' adult cases presented cells immunostained for GST-pi throughout the thickness of the mucosa, including the basal layer. Some non-neoplastic conditions like inflammation, repair and metaplasia and some dysplastic and neoplastic lesions showed areas of positively stained cells within an otherwise negative tissue, indicating a phenotypic heterogeneity regarding the enzyme expression. Our results confirm that GST-pi has a fetal character and indicate that it may appear in the adult cervical squamous epithelia under 'normal' or pathological conditions not necessarily linked to the process of carcinogenesis. Therefore it cannot be used as a marker for cervical epithelial neoplasia.

Biomarkers↗
PubMed1989

Modifying influence of dehydroepiandrosterone or butylated hydroxytoluene treatment on initiation and development stages of azaserine-induced acinar pancreatic preneoplastic lesions in the rat.

Dietary administration of dehydroepiandrosterone (DHEA) (0.6%) or butylated hydroxytoluene (BHT) (1%) during or subsequent to two i.p. injections of azaserine (30 mg/kg body wt) resulted in significant alteration of yield of preneoplastic lesions in both pancreas and liver. While concomitant application appeared not to have any effect on subsequent development of glutathione S-transferase P form (GST-P) positive hepatocellular lesions in either case, BHT and to a lesser extent also DHEA reduced initiation of pancreatic acinar carcinogenesis. Both BHT and DHEA were associated with significant increase in GST-A form positive pancreatic foci when administered after cessation of carcinogen treatment while clearly inhibiting liver lesion development. The results point to a marked differential in the response of the liver and pancreas to external stimulus with regard to preneoplastic focal lesions while demonstrating significant second stage promotion of pancreatic acinar carcinogenesis by BHT and DHEA.

Animals↗
PubMed1989

Proliferation kinetics of pepsinogen altered pyloric gland cells in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine.

The cell kinetics of pepsinogen isozyme 1 altered pyloric gland (PAPG) cells with low pepsinogen isozyme 1 (Pg 1) content were analysed using double immunohistochemical staining for bromodeoxyuridine (BrdU) incorporation and Pg 1 in male WKY/NCrj rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After administration of 100 micrograms/ml MNNG for 10 weeks in the drinking water, carcinogenic insult was terminated and the animals killed two weeks later. BrdU was given either as a single i.p. injection (100 mg/kg b.w.) 1 h prior to death or continuously by osmotic minipump (120 micrograms/h) for 4, 7 and 10 days before killing. Immunogold-silver staining was used to detect BrdU and the avidin-biotin-peroxidase complex method adopted for demonstration of Pg 1. PAPG were found only in the MNNG treated group: their frequency was 4.1 +/- 0.6 per 100 pyloric glands. Almost no normal pyloric gland cells with high Pg 1 content demonstrated incorporation after BrdU flash labelling. However, a few pyloric gland cells in PAPG were labelled. The number of labelled cells in the pyloric columns containing PAPG was larger (P less than 0.05) than in normal pyloric columns. After continuous BrdU administration, the life span of cells comprising PAPG was estimated to be approximately 6-8 days while that of normal pyloric gland cells was approximately 11-13 days. Thus, the data indicate that PAPG cells demonstrate a degree of independence from surrounding pyloric glands with regard to proliferation kinetics, suggesting that PAPG is a preneoplastic lesion involved in gastric carcinogenesis.

Animals↗
PubMed1989

Pyloric gland phenotypic expression of gastric cancers developing in the rat fundic glandular stomach.

Mucin histochemistry of experimental gastric cancers induced in rats by N-methyl-N'-nitro-N-nitrosoguanidine or 4-nitroquinoline 1-oxide was analysed by labelled lectin staining for concanavalin A (Con A) after prior periodate oxidation (paradoxical Con A staining) or Arachis hypogarea agglutinin (peanut lectin, PNA) with or without prior periodate oxidation. In the digestive tracts of control-group rats the mucins were classified into class II or III by paradoxical Con A staining. Class II mucins were found in surface mucous cells, goblet cells and the surface coat of intestinal absorptive cells, while class III mucins were present in mucous neck cells, pyloric gland cells and Brunner's gland cells. Although class III mucins showed PNA reactivity, those in pyloric gland cells selectively lost positive staining after 1-4 h oxidation with periodate. Thus phenotypic expression of class III mucin-positive cells in the gastric mucosa could be further classified into mucous-neck-cell type and pyloric-gland-cell type on the basis of this sensitivity to periodate oxidation. Metaplastic cells in fundic mucosa and almost all class III mucin-positive cells in adenomatous hyperplasias, well-differentiated adenocarcinomas and signet-ring cell carcinomas, which developed in both fundic and pyloric mucosae, showed pyloric gland phenotypic expression.

4-Nitroquinoline-1-oxide↗
PubMed1989

Pancreatic acinar cell tumors in rats induced by 3,2'-dimethyl-4-aminobiphenyl.

Pancreatic acinar cell lesions, including foci, nodules, adenomas and in situ carcinomas, were found in male F344 rats given s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) at doses ranging from 50 to 167 mg/kg body weight in two 60-week experiments. The pancreatic lesions induced by DMAB were essentially the same as those reported in rats treated with 4-hydroxyaminoquinoline-1-oxide and azaserine. DMAB at high doses induced pancreas acinar cell as well as fat necrosis, and tumorigenicity for the pancreas was most effective at high necrogenic levels of carcinogen exposure. Mean labeling indices in basophilic foci, acidophilic foci, nodules and adenomas assessed by bromodeoxyuridine incorporation were elevated to approximately 0.69, approximately 2.17, approximately 1.43 and approximately 0.96% respectively, in contrast to the value of 0.39% observed for the surrounding normal acinar cells. The increase was significant in the acidophilic foci and nodules and the fact that these lesions had very high labeling indices suggests that they may have potential for progression to tumors.

Adenoma↗
PubMed1989

Preparation and characterization of antibodies against 3,2'-dimethyl-4-aminobiphenyl-modified DNA.

Polyclonal antibodies for 3,2'-dimethyl-4-aminobiphenyl (DMAB)-DNA adducts were obtained from the sera of rabbits immunized with N-OH-DMAB-modified DNA. Using the enzyme linked immunosorbent assay (ELISA), these antibodies were shown to recognize DNA modified by N-OH-DMAB and N-hydroxy-4-aminobiphenyl, but not unmodified DNA, 2-acetylaminofluorene- or 4-nitroquinoline-1-oxide-modified DNA, free aminobiphenyl or DMAB derivatives. Using competitive ELISA with DMAB-modified denatured DNA, a 50% inhibition of antibody antigen binding was caused by 7 fmol of DMAB adducts applied to each assay well as an inhibitor. Native DNA bearing adducts was associated with 50% inhibition in the range of 22-90 fmol/asay well, depending on the levels of modification. The adducts recognized by the antibody were shown to be stable against treatment of heat or alkali denaturation. Optimal conditions for the detection of adducts in DNA from the rat organs exposed to DMAB were established by means of competitive ELISA, using alkaline-denatured DNA as an inhibitor. Thus, as little as 5 fmol adducts in 1 microgram of DNA could be detected. Indirect immunofluorescence staining indicated that anti-DMAB-DNA antibodies bound specifically to nuclear components of rat fibroblast 3Y1 cells treated with N-OH-DMAB. The intensity of the fluorescence was proportional to the dose of carcinogen administered. The antibodies should be helpful for use in studies on the formation of adducts and their removal in cells and tissues after DMAB administration.

Aminobiphenyl Compounds↗
PubMed1989

Co-carcinogenic effects of NaHCO3 on o-phenylphenol-induced rat bladder carcinogenesis.

The role of urinary pH and Na+ concentration on the bladder carcinogenesis of o-phenylphenol (OPP) was examined in male F344 rats. The rats were given powdered diet containing 2% sodium o-phenylphenate (OPP-Na, group 1), 1.25% OPP plus 0.64% NaHCO3 (group 2), 1.25% OPP plus 0.32% NaHCO3 (group 3), 1.25% OPP plus 0.16% NaHCO3 (group 4), 1.25% OPP (group 5), 0.64% NaHCO3 (group 6) or no test chemical (group 7) for 104 weeks respectively. Incidences of bladder carcinoma induced were significantly higher in groups 1 (12 of 29 rats, 41.4%) and 2 (9 of 29 rats, 31.0%) than in group 7 (0 of 27 rats, 0%). Groups 3 and 4 induced bladder carcinomas in 4 of 29 rats (13.8%) and 4 of 26 rats (15.4%) respectively, whereas no tumors occurred in group 5 (0 of 27, 0%). The incidence in group 6 was 3.6% (1 of 28 rats). Groups 1 and 2 induced significant increases in urinary pH and Na+ concentrations, whereas group 5 did not. Groups 3 and 4 showed the same tendency as groups 1 and 2. Examination with a scanning electron microscope showed the appearance of pleomorphic microvilli, short, uniform microvilli, and ropy or leafy microridges on the luminal surface of the bladder in groups 1-5 of rats treated with OPP or OPP-Na for 8 weeks. The appearance and severity were the same in groups 1 and 2, followed by the groups with decreasing doses of NaHCO3. The results indicated that OPP-Na is carcinogenic for the rat bladder, but OPP is not. However, increased urinary pH and Na+ concentration play important roles in OPP-Na rat bladder carcinogenesis.

Animals↗