Biomedical subjects

Y Takesada

Publications and source records attributed to Y Takesada.

12 recordsLinked to original sources

PubMed1998

Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4-methoxyphenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi-organ carcinogenesis model.

The carcinogenicity of low dietary levels of the antioxidants butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and catechol, known to target the forestomach or glandular stomach, were examined alone or in combination in a 2-year long-term experiment and their modifying effects assessed in a medium-term multiorgan model. In the carcinogenicity study, groups of 30-31 male F344 rats were treated with 0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol either alone or in combination for up to 104 weeks and then killed. In the medium-term multi-organ model, groups of 10 to 15 male F344 rats were given diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or 0.032% were administered in the diet either alone or in combination after completion of the initiation regimen. All surviving animals were killed at the end of week 28, and major organs were examined histopathologically. In the carcinogenicity study, slightly increased incidences of forestomach papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%), catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet (0%), and a significant increase was observed with the five antioxidants in combination (42.9%, P < 0.001). In a medium-term multiorgan carcinogenesis model, incidences of forestomach papillomas and/or carcinomas were increased in each high dose group, but additive or synergistic effects were not found in the combination group. In the low dose case, the incidence of forestomach papillomas was significantly increased only in the combination group. With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group. The results indicate that even at low dose levels phenolic compounds can exert additive/synergistic effect on carcinogenesis.

Animals↗

PubMed1997

Post-initiation inhibitory effects of green tea catechins on 7,12-dimethylbenz[a]anthracene-induced mammary gland carcinogenesis in female Sprague-Dawley rats.

The dose-dependence of green tea catechin (GTC) effects on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary gland carcinogenesis were investigated in female Sprague-Dawley rats. Groups of 20 6-week-old rats were treated with dietary 1, 0.1 or 0.01% GTC for 2 weeks and then basal diet alone for 35 weeks. At the end of week 1, they received a 25 mg/kg body weight intragastric dose of DMBA. Further groups of 20 7-week-old rats each were given an intragastric dose of 25 mg/kg body weight DMBA, and starting 1 week after DMBA treatment they were placed on diet containing 1, 0.1 or 0.01% GTC or basal diet alone for 35 weeks. Control rats were given 1% GTC or basal diet alone. The final incidences and multiplicities of mammary tumors were not significantly different between the groups treated with GTC at the same time as DMBA, compared to the DMBA alone control group. On the other hand, the final multiplicities of mammary tumors in groups treated with 1% GTC (P < 0.05) or 0.01% GTC (P < 0.01), but not 0.1% GTC, after DMBA treatment were significantly decreased as compared to the control value. These results indicate that whereas GTC may inhibit mammary carcinogenesis in the post-initiation stage, the effect is weak and not dose-dependent.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Effects of tamoxifen, an antiestrogen, on rat prostate carcinogenesis by 3,2'-dimethyl-4-aminobiphenyl and testosterone do not support an estrogen role in testosterone promotion.

BACKGROUND: Our previous data suggest that estrogen plays an important role in rat prostate carcinogenesis, particularly in promotion by testosterone. Therefore, in the present experiment, effects of an antiestrogen, tamoxifen (TAM), were investigated. METHODS: Male F344 rats initially received 3,2'-dimethyl-4-aminobiphenyl (DMAB) at 50 mg/kg bw every 2 weeks for 20 weeks and then TAM in Silastic tubes was subcutaneously given alone or together with testosterone propionate (TP) for 40 weeks. RESULTS: TAM significantly suppressed prostate weights, suggesting an estrogenic action, but the development of preneoplastic and/or neoplastic lesions of the prostate or seminal vesicles in rats given DMAB alone or DMAB and TP was not altered. TAM reversed the suppression of development of ventral atypical hyperplasias by TP. CONCLUSIONS: These findings suggest that estrogen, which is derived from testosterone by the action of aromatase, is not involved in the strong promotion by TP of DMAB prostate carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Decrease of prostaglandin E2 and 5-bromo-2'-deoxyuridine labeling but not prostate tumor development by indomethacin treatment of rats given 3,2'-dimethyl-4-aminobiphenyl and testosterone propionate.

The modifying effects of indomethacin (IM) on rat prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) were investigated. F344 rats were given 50 mg/kg body weight of DMAB at 2-week intervals for 20 weeks and then received IM at a dose of 20 ppm in the drinking water for 37 weeks. Separate groups additionally received testosterone propionate (TP) in Silastic tubes throughout the experiment. DMAB alone induced carcinomas in situ in the ventral lobe and in combination with TP caused invasive carcinomas of the dorso-lateral and anterior lobes and seminal vesicles. No clear suppression by IM of development of in situ carcinomas or invasive carcinomas was observed. In a short-term satellite experiment, it was revealed that prostaglandin E2 (PGE2) levels in the dorso-lateral prostate and seminal vesicles, but not the ventral prostate, were significantly reduced by IM and that TP itself also suppressed PGE2 levels. The 5-bromo-2'-deoxyuridine labeling index in the ventral prostate was significantly decreased by IM administration. These results indicate that while IM can efficiently suppress tissue PGE2 levels, it does not inhibit tumor development in the prostate or seminal vesicles of rats in the present model.

Aminobiphenyl Compounds↗

PubMed1996

Dose-related increases in quantitative values for altered hepatocytic foci and cytochrome P-450 levels in the livers of rats exposed to phenobarbital in a medium-term bioassay.

The dose-response relationship between liver tumor promoting activity and cytochrome P-450 (CYP) induction by phenobarbital sodium (PB) was investigated using the liver medium-term bioassay system of Ito. Two weeks after a single dose of N-nitrosodiethylamine (DEN) (200 mg/kg body weight, i.p.), rats were given PB at dietary levels of 500, 250, 125, 60, 30, 15 and 8 parts per million (ppm) for 6 weeks. All rats were subjected to partial hepatectomy at week 3, and were killed at week 8. Quantitative values for glutathione S-transferase placental form positive hepatocytic (GST-P+) foci were increased in the high dose groups dose-dependently. In contrast, the values in the low dose groups were rather lower than that of the control. CYP2B1, 2C6 and 3A2 were predominantly immunostainable in hepatocytes around the central vein. While Western blotting revealed CYP2B1 and 2C6 proteins to be increased with strict dose-dependence, CYP3A2 was only elevated at high doses. Thus, a good correlation between increase of GST-P+ foci and CYP3A2 induction was observed, as well as with CYP2B1 and 2C6 in high dose groups.

Animals↗

PubMed1996

Lack of tumor promoting effects of KCB-1, a recombinant human basic fibroblast growth factor, on two-stage skin carcinogenesis in female CD-1 (ICR) mice.

Skin tumor promoting and co-promoting potentials of KCB-1, a recombinant human basic fibroblast growth factor, were investigated in a two-stage skin carcinogenesis model using female ICR mice. Animals were allocated to either normal (non-injured) or injured skin groups, and given a single topical application of dimethylbenz[alpha]anthracene (DMBA) at 100 micrograms/mouse to fur-clipped back skin. One week after the DMBA initiation step, mice were injected with KCB-1 (0.4, 4.0 and 40 micrograms/mouse, s.c.) and/or 12-O-tetradecanoylphorbol-13-acetate (TPA) at 4.0 micrograms/mouse twice a week until the termination at week 20. The treatment with KCB-1 was not associated with any increases of papillomas and hyperplasias in either the normal or the wounded skin cases. High incidences and multiplicities of skin papillomas and hyperplasias developed in TPA-treated groups. The positive control TPA promotion was not influenced by the KCB-1 treatment in the present initiation/promotion protocol. Thus, KCB-1 exerted no tumor promoting effects on mouse skin two-stage carcinogenesis, and also no amplification activity for the established skin tumor promoter TPA.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1996

Effects of carbamate insecticides in a rat medium-term bioassay for hepatocarcinogens.

Ethiofencarb and pirimicarb, widely used insecticides, were investigated for hepatocarcinogenesis-modifying effects using a medium-term bioassay system for carcinogens. F344 male rats were given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and then, starting 2 wk later, received ethiofencarb in the diet at concentrations of 500 or 250 ppm, pirimicarb at 400 or 200 ppm, or a combination of ethiofencarb (250 ppm) and pirimicarb (200 ppm) for 6 wk. Control groups received DEN (200 mg/kg) or carbamate insecticides alone as stated earlier, without DEN. All rats were subjected to two-thirds partial hepatectomy at wk 3 and were killed at wk 8. Development of preneoplastic lesions, glutathione S-transferase placental form-positive foci, in the liver was significantly increased in terms of number receiving 500 ppm ethiofencarb. The results thus indicate that ethiofencarb at high dose possesses promoting activity for rat liver carcinogenesis.

Animals↗

PubMed1996

Subchronic toxicity study of L-isoleucine in F344 rats.

A subchronic toxicity study with L-isoleucine was conducted using F344 rats. Groups of 10 rats of each sex were given diet containing 0, 1.25, 2.5, 5.0, or 8.0% L-isoleucine for 13 wk. No treatment-related effects were observed in terms of body weight change, food consumption or hematology. In both sexes given 8.0% L-isoleucine, increased or a tendency for increased urine volume and relative kidney weights were observed. Furthermore, the high-dose L-isoleucine treatment brought about an elevation of urinary pH and variations in serum electrolytes. However, histopathological alterations related to these changes were not observed in any organs of either sex. In conclusion, the present study demonstrated that L-isoleucine possessed minimal toxicity at dietary levels of 5.0% and 8.0%, while it did not exert any adverse affects at a dietary level of 2.5% or less.

Animals↗

PubMed1996

Inhibitory effects of phenolic compounds on development of naturally occurring preneoplastic hepatocytic foci in long-term feeding studies using male F344 rats.

Five phenolic compounds, namely caffeic acid, sesamol, hydroquinone, catechol, and 4-methoxyphenol, were fed to groups of 30 male F344 rats at dietary levels of 2, 2, 0.3, 0.8, and 2%, respectively, for 2 years. Retardation of body weight and elevated relative liver weights were noted for all groups. Formalin-fixed and paraffin-embedded liver tissues from rats killed terminally were cut and stained for glutathione S-transferase placental form (GST-P) and tumor growth factor alpha (TGF alpha) immunohistochemically. Numbers and areas of GST-P-positive (GST-P+) foci per unit area of liver section were measured, and the respective treated/control proportional values were calculated to be 58 and 57% for caffeic acid. 58 and 54% for sesamol, 71 and 71% for hydroquinone. 58 and 133% for catechol, and 49 and 39% for 4-methoxyphenol. These data were comparable with results obtained with medium-term liver bioassays (Ito test). However, no intergroup differences were detected with regard to quantitative findings for TGF alpha foci, which were relatively rare. Long-term inhibitory effects of phenolic compounds on liver carcinogenesis, predicted from the Ito test, were thus confirmed in the present feeding studies using quantitative analysis of immunohistochemically demonstrable GST-P+ foci as end point marker lesions.

Animals↗

PubMed1994

Progressive growth of rat bladder carcinomas after exposure to prolonged uracil-induced urolithiasis.

Dietary uracil at the 3% level induces urinary bladder tumors in rats through urolithiasis-dependent mechanical irritation. In the present study, comparison of lesions induced by uracil administration over the different periods of 36 weeks (middle-term) and up to 103 weeks (long-term) revealed significant elevation of both incidences and multiplicity of transitional cell carcinomas (TCCs) in the long-term group. Histopathological assessment in terms of tumor biology further demonstrated significantly higher grading on the basis of the degree of cellular and structural atypia, and greater depth of invasion in the long-term group. Application of markers for cell proliferation activities including proliferating cell nuclear antigen (PCNA) and silver-binding nucleolar organizer regions (AgNORs) also revealed significantly elevated AgNOR counts in the long-term group TCC. AgNOR counts and PCNA rates in TCCs showed relation to the histological grades. Thus the present study demonstrated that prolonged uracil-induced urolithiasis causes more biologically aggressive bladder carcinomas with invasive potential. Continuous stimulation of cell proliferation presumably has the potential to facilitate multiple genetic alterations leading to development of more malignant carcinomas. However, it should be borne in mind that the difference in bladder cancer development might also be related to the fact that the animals survived longer and that the early lesions therefore had more time to progress to more advanced stages.

Animals↗

PubMed1993

Chemoprevention by indomethacin of tumor promotion in a rat urinary bladder carcinogenesis model.

The chemopreventive effects of indomethacin (IM) on the enhancement of bladder carcinogenesis and transitional-epithelial-cell proliferation by butylated hydroxyanisole (BHA) or sodium L-ascorbate (Na-AsA) were investigated. All animals were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks. They then received 2% BHA or 5% Na-AsA for 20 weeks, followed by 20 ppm IM in the drinking water or normal tap water without supplement for a further 20 weeks, or BHA or Na-AsA alone or concomitantly with IM for 40 weeks. No differences in bladder-tumor development were found when IM was administered after cessation of BHA or Na-AsA exposure. However, IM in combination with either BHA or Na-AsA significantly reduced both the incidence and the multiplicity of papillomas and carcinomas as compared with the values of groups receiving BHA or Na-AsA alone. This was associated with decreased DNA synthesis and prostaglandin (PG) E2 levels in the existing bladder tumors. Combined treatment with IM did not exert any effects on BHA forestomach carcinogenesis. A separate 8-week combination study demonstrated that IM diminished the increase in expression of proliferation nuclear-cell antigen (PCNA) induced by BHA or Na-AsA alone. The present results suggest that PGE2 may be involved in promotion of rat bladder carcinogenesis and that the PG synthesis blocker IM might exert preventive effects on the development of bladder cancer in humans.

Animals↗

PubMed1992

Action of neopullulanase. Neopullulanase catalyzes both hydrolysis and transglycosylation at alpha-(1----4)- and alpha-(1----6)-glucosidic linkages.

The transglycosylation reaction catalyzed by neopullulanase was analyzed. Radioactive oligosaccharides were produced when the enzyme acted on maltotriose in the presence of [U-14C]glucose. Some of the radioactive oligosaccharides had only alpha-(1----4)-glucosidic linkages, but others were suggested to have alpha-(1----6)-glucosidic linkages. The existence of alpha-(1----6)-glucosidic linkages in the products from maltotriose with neopullulanase was proven by proton NMR spectroscopy and methylation analysis. We previously reported that the one active center of neopullulanase catalyzes the hydrolysis of alpha-(1----4)- and alpha-(1----6)-glucosidic linkages (Kuriki, T., Takata, H., Okada, S., and Imanaka, T. (1991) J. Bacteriol. 173,6147-6152). These facts proved that neopullulanase catalyzed all four types of reactions: hydrolysis of alpha-(1----4)-glucosidic linkage, hydrolysis of alpha-(1----6)-glucosidic linkage, transglycosylation to form alpha-(1----4)-glucosidic linkage, and transglycosylation to form alpha-(1----6)-glucosidic linkage. The four reactions are typically catalyzed by alpha-amylase, pullulanase, cyclomaltodextrin glucanotransferase, and 1,4-alpha-D-glucan branching enzyme, respectively. These four enzymes have some structural similarities to one other, but reactions catalyzed by the enzymes are considered to be distinctive: the four reactions are individually catalyzed by each of the enzymes. The experimental results obtained from the analysis of the reaction of the neopullulanase exhibited that the four reactions can be catalyzed in the same mechanism.

1,4-alpha-Glucan Branching Enzyme↗