Biomedical subjects

N Ito

Publications and source records attributed to N Ito.

At least 613 records · Page 34Linked to original sources

PubMed1987

Metabolism of 2- and 3-tert-butyl-4-hydroxyanisole (2- and 3-BHA) in the rat (I): Excretion of BHA in urine, feces and expired air and distribution of BHA in the main organs.

The mechanism of the carcinogenic or toxic action of BHA on rat forestomach was examined by studies on the excretion and tissue distribution of radioactivity in F344 male rats given tert-butyl- or methoxy-labelled 3-BHA orally. Within 2 days after a single oral dose of labelled BHA at 1 g/kg body wt, 87-96% of the 14C was excreted, mainly in the urine with smaller amounts in the feces and expired air. More 14C was found in the tissues of rats given the methoxy-labelled compounds. The distributions of 14C in the forestomach and the glandular stomach were similar. At 168 h after treatment, more 14C was found in the forestomach of rats given 2-BHA than in that of rats given 3-BHA. These results indicate that excretion of BHA is rapid, that 4-O-methyl demethylation may take place readily and that demethylated methyl group may become distributed non-specifically in tissues. The carcinogenic or toxic action of BHA on the forestomach does not seem to be due accumulation of BHA in the forestomach.

Air↗

PubMed1987

Metabolism of 2- and 3-tert-butyl-4-hydroxyanisole (2- and 3-BHA) in the rat. (II): Metabolism in forestomach and covalent binding to tissue macromolecules.

The mechanism of action of 2(3)-tert-butyl-4-hydroxyanisole (2-BHA or 3-BHA) on rat forestomach epithelium was studied by examining the metabolites of BHA in the stomach and the covalent binding of BHA to macromolecules in the forestomach epithelium. Male F344 rats 6 weeks old were given a single intragastric injection of 1 g/kg body wt of [tert-14C]-3-BHA (Bu-3-BHA) or [methyl-14C]-3-BHA (Me-3-BHA), and 6 h later BHA metabolites in the forestomach, glandular stomach and stomach contents were examined by thin-layer chromatography. No significant amounts of metabolites were detected in the forestomach or glandular stomach epithelium and almost all the radioactivity in these tissues was extracted with organic solvents. In in vitro experiments also, no significant amounts of metabolites were detected when the 9000 g supernatant of the forestomach or glandular stomach epithelium, or gastric juice was incubated with Bu-3-BHA in the absence or presence of NADPH. In binding studies, rats were given Bu-3-BHA, [tert-14C]-2-BHA (Bu-2-BHA), Me-3-BHA or [methyl-14C] butylated hydroxytoluene (Me-BHT) intragastrically at a dose of 1 g/kg body wt with or without pretreatment with unlabelled 1% 3-BHA or BHT in the diet for 6 days. Six hours after treatment with a labelled compound, the rats were sacrificed and the DNA, RNA and protein of their forestomach, glandular stomach, liver and kidney were isolated. Bu-3-BHA, Bu-2-BHA and Me-3-BHA did not bind covalently to forestomach DNA or RNA, and the amounts of radioactivity of these compounds bound to proteins in the 4 tissues were similar. These findings suggest that BHA acts on the forestomach epithelium directly without metabolic activation, and that its action is not related to its binding to DNA or RNA.

Animals↗

PubMed1987

Lack of tumorigenic response in the prostate gland of castrated F344 rats by 3,2'-dimethyl-4-aminobiphenyl given with methyltestosterone.

In an attempt to induce a high incidence of prostate carcinoma, 3,2'-dimethyl-4-aminobiphenyl (DMAB), a prostatic carcinogen, was given during the period of cell proliferation of the prostate gland induced by the administration of methyltestosterone (MT) to castrated F344 rats. Three weeks after the surgical castration, rats were given diet containing 300 ppm of MT for 2 weeks and basal for 2 weeks alternately 12 times. During each treatment with MT, one (group 1) or two (group 2) subcutaneous injections of 50 mg/kg body wt. of DMAB was given. After the last treatment of MT, a pellet of testosterone propionate (TP) was implanted in the subcutis of all animals until the end of the experiment (week 60). No carcinomas developed in the prostate gland of any of the rats. Atypical hyperplasia of the ventral lobe of prostate was found in 4 of 22 rats in group 1 and 2 of 20 rats in group 2. The incidences of atypical hyperplasia of the seminal vesicles in groups 1 and 2 were 64% and 75%, respectively. No pathological lesions in the prostate were observed in 32 rats given DMAB without MT treatment.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1987

Lesions of the prostate glands and seminal vesicles induced by N-methylnitrosourea in F344 rats pretreated with ethinyl estradiol.

In an attempt to induce a high incidence of prostate carcinoma, N-methylnitrosourea (MNU), a multipotential carcinogen, was given during the period of cell proliferation of the prostate gland induced by administration of methyltestosterone (MT) to F344 rats pretreated with ethinyl estradiol (EE). Rats were given diet containing EE for 3 weeks and then diet containing 300 ppm of MT for 5 days. On the 3rd day of MT-treatment, they were given a single intravenous injection of 50 mg/kg body wt. of MNU. Control rats (group 4) were given vehicle only. After treatment with MT for 5 days, the rats were given basal diet (group 1), diet containing MT (group 2) or diet periodically containing EE (groups 3 and 4) until the end of the experiment (week 60). Carcinoma of the prostate was found only in 1 of 17 rats in group 3. Atypical hyperplasia of the prostate was found in 1 of 10 rats in group 1 and 3 of 17 rats in group 2. The incidences of atypical hyperplasia of the seminal vesicles in groups 1-3 were 0%, 41% and 29%, respectively. No tumor promoting effect of MT or EE was observed except promotion by MT on the development of atypical hyperplasia of the seminal vesicles.

Animals↗

PubMed1987

Modification by alpha-tocopherol, propyl gallate and tertiary butylhydroquinone of urinary bladder carcinogenesis in Fischer 344 rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The promoting activity of 3 antioxidants, alpha-tocopherol (alpha-TP), propyl gallate (PG) and tertiary butylhydroquinone (TBHQ) in urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats was examined. Rats, 6-week-old, were treated with 0.05% BBN in the drinking water for 4 weeks and then administered 1.50, 0.75 or 0.38% alpha-TP, 1.0% PG or 2.0% TBHQ in the diet for 32 weeks. The urinary bladder of all animals was examined histologically after the total 36 experimental weeks. The incidence of papillary or nodular hyperplasia (PN hyperplasia) of the urinary bladder was significantly higher in the rats treated with BBN followed by 2.0% dietary TBHQ that in controls initiated with 0.05% BBN followed by control diet. This result indicates that TBHQ has weak promoting activity in urinary bladder carcinogenesis. alpha-TP and PG did not demonstrate a promoting effect for urinary bladder lesions.

Animals↗

PubMed1987

Dose-dependent effects of butylated hydroxyanisole, butylated hydroxytoluene and ethoxyquin for promotion of bladder carcinogenesis in N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated, unilaterally ureter-ligated rats.

Dose-dependent effects of 3 antioxidants, butylated hydroxyanisole (BHA, 2.0, 1.0 and 0.5%), butylated hydroxytoluene (BHT, 1, 0.5 and 0.25%) and ethoxyquin (0.5, 0.25 and 0.125%) on the development of preneoplastic lesions in the bladder of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-treated rats were investigated. Feeding of the antioxidants after pretreatment of 0.05% BBN commenced and unilateral ureteric ligation was combined at week 3 of the experiment. Surviving rats were killed at the end of week 24. BHA and BHT, but not ethoxyquin increased dose-dependently the incidence and number of preneoplastic lesions, papillary or nodular hyperplasia of the urinary bladder in rats treated with BBN. Particularly, the incidence and number of PN hyperplasia in rats treated with 2.0% BHA and 1.0% BHT were significantly higher than those of the control group. Thus, promoting activities of BHA and BHT, but not ethoxyquin for the urinary bladder were confirmed in this system of BBN-initiated, unilaterally ureter-ligated rats.

Animals↗

PubMed1987

Proliferative response of rat accessory sex organs to dietary sex hormones after castration or initial dietary administration of estrogen.

The hormone dependent proliferative response of five accessory sex organs was examined subsequent to castration-induced or estrogen-induced atrophy using male six-week-old F344 rats. Three weeks after castration, rats were treated with dietary methyltestosterone (300 ppm), ethinyl estradiol (0.75 ppm) or methyltestosterone plus ethinyl estradiol for up to 17 days. Cell proliferation was assessed by 3H-thymidine incorporation as determined from labelling indices using autoradiography. The maximum labelling indices which appeared on days 2 or 3 of administration of methyltestosterone were 24.3, 8.4, 9.6, 21.6 and 13.7% for the ventral, lateral and dorsal prostate, seminal vesicle and coagulating glands, respectively. Combined methyltestosterone and ethinyl estradiol induced mild proliferative responses whereas ethinyl estradiol did not. In a further group of non-castrated rats which were pretreated with dietary ethinyl estradiol for three weeks and then given methyltestosterone, the maximum labelling indices were about 70 to 80% of that in castrated rats.

Animals↗

PubMed1987

13-week subchronic toxicity study with morpholine oleic acid salt administered to B6C3F1 mice.

The effect of subchronic administration of morpholine oleic acid salt (MOAS) was studied in B6C3F1 mice. The dose levels of MOAS used were 0%, 0.15%, 0.3%, 0.6%, 1.25%, and 2.5% in drinking water. Reduced weight gains were noted in both sexes in the 2.5% group as compared to controls, but reductions were not significant. Water consumption values showed a dose-related tendency for a decrease in both females and males. Urine analysis showed significant elevation of specific gravity in the males in the 0.6%, 1.25%, and 2.5% groups and the females in the 1.25% and 2.5% groups. Significant elevation of plasma urea nitrogen was observed in males of the 1.25% and 2.5% groups and in females of the 0.6%, 1.25%, and 2.5% groups. The relative weight of the kidneys showed a dose-dependent increase that was statistically significant for the 1.25% and 2.5% MOAS groups in both sexes. Except for cloudy swelling of the proximal tubules of the kidneys in mice on the 2.5% regimen, no treatment-related histopathological alterations were observed in organs of either sex.

Animals↗

PubMed1987

Hereditary generalized amyloidosis with polyneuropathy. Clinicopathological study of 65 Japanese patients.

A clinicopathological study was made on 65 patients from a small area of Nagano Prefecture, Japan, with hereditary generalized amyloidosis with polyneuropathy to clarify the clinical variety of the disease. Forty-five patients from Ogawa village showed similar clinical features. The age of onset ranged widely from 16 to 62 years. The main neurological manifestations were polyneuropathy starting in the legs and autonomic dysfunction. Lower cranial nerves were also affected in the advanced stages. Severe cardiac and renal involvement was uncommon. All these clinical features are consistent with type I familial amyloid polyneuropathy (FAP). The remaining 20 patients from five unrelated kinships showed unique clinical pictures. Two families from Ogawa village had type I FAP, but 4 out of the 5 affected patients showed marked nephropathy with heavy proteinuria from an early stage. Of the three other families, one, with 10 patients, was notable for the involvement of the central nervous system. Most of the patients showed cerebellar ataxia and pyramidal tract signs in addition to a sensorimotor and autonomic peripheral neuropathy. Another family had 2 siblings who had severe amyloid heart disease from the onset and developed polyneuropathy with autonomic features at an advanced stage. In the third family, onset occurred in the sixth decade in all 3 patients and the course was mild in 2, although the clinical features were those of typical type I FAP. Immunohistochemical study revealed that the amyloid fibril proteins in the patients with all four unusual clinical phenotypes were related to plasma prealbumin. The most common form of hereditary generalized amyloidosis in Japan is type I FAP, but the disease shows considerable variety in the age of onset and involves more systemic organs than previously recognized. The newly recognized clinical forms of hereditary generalized amyloidosis with severe amyloid heart disease or central nervous dysfunction indicate clinical heterogeneity of hereditary amyloidosis with polyneuropathy.

Adolescent↗

PubMed1987

Organ specific modifying potential of ethinyl estradiol on carcinogenesis initiated with different carcinogens.

Estrogen has been shown to exert a modifying potential on carcinogenesis in various organs, and in particular the hormone-dependent tissues. The present experiments were carried out to determine the effects of post-initiation phase administration of ethinyl estradiol (EE) on tumor development in the liver, kidney, lung, thyroid, bladder and esophagus of male F344 rats. Animals were initiated by 2 weeks treatment with 0.05% N-bis(2-hydroxypropyl)nitrosamine (DHPN), 0.1% N-ethyl-N-hydroxyethylnitrosamine (EHEN), 0.03% N-nitrosopiperidine (NPD), 0.02% 2-acetylaminofluorene (2-AAF) or 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their diet or drinking water, and starting 1 week after initiation, they were given diet with or without a 0.001% EE supplement for 49 weeks, at which point the experiment was terminated. EE significantly increased the development of tumors of the liver (DHPN-, EHEN-, 2-AAF- and NPD-treated groups) and kidneys (EHEN-treated group) but inhibited their development in the lungs (DHPN-treated group) and urinary bladder (BBN-treated group). In the liver, EE also increased the development of glutathione S-transferase P type-positive lesions to various extents depending on the initiator used. EE administration was associated with a decreased incidence of esophageal hyperplasia in the EHEN-initiated group but an opposite increase in the NPD-initiated animals. No effect of EE was evident regarding thyroid lesions.

2-Acetylaminofluorene↗

PubMed1987

Effects of simultaneous treatment with various chemicals on BHA-induced development of rat forestomach hyperplasia--complete inhibition by diethylmaleate in a 5-week feeding study.

Male F344 rats were administered phenobarbital, polychlorinated biphenyl (PCB), retinol acetate, indomethacin, 6-amino-caproic acid, dexamethasone (DEX) or diethylmaleate (DEM) for one week and then were treated with these chemicals plus butylated hydroxyanisole (BHA) for a further four weeks. Histopathologically, the incidence of BHA-induced forestomach hyperplasia was significantly lower in rats treated with PCB, DEX or DEM than in those treated with BHA alone. However, the inhibition by PCB and DEX was only partial and might have been due to decreased food intake. On the other hand, DEM completely inhibited the hyperplastic response to BHA at a dose of 0.25%, and even at lower doses it demonstrated significant inhibition without any decrease in body weight or food intake. The result that DEM, a tissue glutathione depleting agent, can inhibit BHA-associated forestomach hyperplasia strongly suggests that tissue glutathione may be intimately involved in the induction of forestomach hyperplasia by the antioxidant in rats.

Aminocaproic Acid↗

PubMed1987

Enhancement of BHA-induced proliferative rat forestomach lesion development by simultaneous treatment with other antioxidants.

Synergistic effects of butylated hydroxyanisole (BHA) and other antioxidants on induction of rat forestomach lesions were investigated. Groups of F344 male rats were treated with 1% BHA plus 0.7% butylated hydroxytoluene (BHT), 1% BHA plus 1% propyl gallate (PG), 1% BHA plus 1% sodium L-ascorbate (SA), 1% BHA plus 1% DL-alpha-tocopherol (alpha-TP), 0.4% BHT plus 0.4% BHA plus 0.4% PG plus 0.4% SA plus 0.4% alpha-TP, 1% BHA or 2% BHA. Further groups of 10 rats each received antioxidants without BHA as controls. Histological examination revealed significantly increased incidences of hyperplasia in the groups given BHA together with SA or PG at the prefundic region or at the mid region respectively. The forestomach changes induced by BHA together with SA were equal to those induced by 2% BHA. On the other hand, simultaneous treatment with BHA and PG or alpha-TP reduced the incidence of hyperplasia at the prefundic region. It is concluded that mixed treatment with BHA and other antioxidants exerted enhancing or inhibitory effects on the induction of hyperplasia at different sites of the forestomach epithelium.

Animals↗

PubMed1987

Immunohistochemically demonstrated altered expression of cytochrome P-450 molecular forms and epoxide hydrolase in N-ethyl-N-hydroxyethylnitrosamine-induced rat kidney and liver lesions.

A comparison of N-ethyl-N-hydroxyethylnistrosamine (EHEN)-induced preneoplastic and neoplastic lesions in the rat liver and kidney was made with respect to the expression of different drug metabolizing enzymes. Four cytochrome P-450 species (cyt. P-450 UT50, PB3a, MC1 and MC2) and microsomal epoxide hydrolase (mEHb) were investigated along with two glutathione S-transferase species (GST-P and A forms) earlier shown to be elevated in putative preneoplastic lesions in the liver and kidney, respectively. In contrast to the liver lesions, which showed clear decrease in all forms of cyt. P-450s and increase of mEHb, elevated levels of cyt. P-450 PB3a and, to a lesser extent, the other P-450 forms and early elevation to late decrease in mEHb characterized the renal tubular lesions. Thus opposite shift in enzyme phenotype was observed in carcinogen-induced focal lesions of the two organs. Variation in binding levels in the different nephron segments and zones of the liver acinus indicated physiological specialization with regard to the enzymes investigated and suggested that the altered phenotype of preneoplastic populations might be of adaptive significance.

Animals↗

PubMed1987

Inhibition of neoplastic development in rat liver, kidney, oesophagus and forestomach by 4,4'-diaminodiphenylmethane administration.

The modifying effects of 4,4'-diaminodiphenylmethane (DDPM) (0.1% in diet) administration on liver carcinogenesis induced by 2-acetylaminofluorene (2-AAF) (0.02% in diet), 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) ( 0.06% in diet), diethylnitrosamine (DEN) (0.001% in drinking water) and N-ethyl-N-hydroxyethylnitrosamine (EHEN) (0.1% in drinking water), EHEN-induced oesophagus and kidney carcinogenesis and forestomach carcinogenesis induced by butylated hydroxyanisole (1.0% in diet) were examined in F344 male rats. Mean survival time tended to be longer in DDPM-supplemented groups, the difference being significant in DEN + DDPM and EHEN + DDPM groups. Intake of carcinogens was slightly but not significantly reduced by DDPM. The incidences of hyperplastic nodules and hepatocellular carcinomas were significantly decreased in 2-AAF or 3'-Me-DAB + DDPM groups. Pulmonary metastases were also less common in 3'-Me-DAB or EHEN + DDPM groups. Development of papillomas in the oesophagus but not in tumours in the forestomach was also inhibited by DDPM. Inhibition in the different organs was not significantly related to decrease in body weight or carcinogen intake, indicating a mechanism independent of non-specific toxic effects or reduction in food consumption. Some other factors possibly related to its ability to cause bile duct proliferation and/or altered activity of enzymes relevant to drug metabolism may be involved.

2-Acetylaminofluorene↗

PubMed1987

Reciprocal modifying effects of isomeric forms of aminophenol on induction of neoplastic lesions in rat liver and kidney initiated by N-ethyl-N-hydroxyethylnitrosamine.

The effects of four isomeric forms of aminophenols, ortho-, meta-, para-aminophenol and acetaminophen (o-, m-, p-AP and AAP, respectively) on liver and kidney carcinogenesis initiated by N-ethyl-N-hydroxyethylnitrosamine (EHEN) were tested. Rats were given 0.1% EHEN (in their drinking water for 2 weeks) and then diet containing these compounds at concentrations of 0.8% for 49 weeks. Administration of o-AP and AAP significantly decreased the number and area of preneoplastic foci staining immunohistochemically for glutathione S-transferase placental type (GST-P) per unit area of liver section as compared with the values for rats given EHEN alone. o-AP and AAP also significantly decreased the incidence of hepatocellular carcinoma. In contrast, p-AP and AAP significantly increased quantitative values for kidney preneoplastic lesions and renal cell adenoma. It is suggested that the cytotoxic effects of these chemicals preferentially suppressed the proliferation of preneoplastic liver cells, but stimulated the mitotic activity of preneoplastic tubular lesions in the kidney.

Acetaminophen↗

PubMed1987

Histochemical demonstration of colonic type mucin in glandular metaplasia and adenocarcinoma of the human urinary bladder.

Mucin in normal, metaplastic and neoplastic tissue specimens of the human urinary bladder was examined histochemically by the periodic acid-borohydride/potassium hydroxide/periodic acid-Schiff (PB/KOH/PAS) reaction and paradoxical concanavalin A (Con A) staining, both of which have been reported to detect mucins that are specific for the lower gastrointestinal tract. Normal mucosa, Brunn's nest, squamous metaplasia, transitional cell carcinoma, and squamous cell carcinoma produced only small amount of mucin and were negative for both PB/KOH/PAS and labile class III by Con A staining. However, several sections of mucin-producing metaplastic bladder lesions and many samples of adenocarcinoma arising from vesical mucosa and urachus contained PB/KOH/PAS-positive and/or labile class III mucin. Thus the colonic type mucin appeared in some materials of both benign and malignant mucin-producing lesions of the urinary bladder. The findings would be related to the embryogenesis of this organ.

Adenocarcinoma↗

PubMed1987

Complete and incomplete pyloric gland metaplasia of human gallbladder.

The features of pyloric gland metaplasia in the gallbladder epithelium were studied by histochemical staining for mucin and the immunoperoxidase method for pepsinogens (Pg) I and II. Pyloric gland metaplasia was found in 48 of 72 gallbladders removed surgically. All the pyloric gland metaplastic cells contained class III mucin demonstrated by paradoxical concanavalin A (Con A) staining. Pyloric gland metaplasia was classified into complete and incomplete types on the basis of the immunohistochemical reactivities of Pgs I and II: The complete type of pyloric gland metaplasia contained neutral mucins and weak Pg I and strong Pg II activities, like normal pyloric gland cells. Almost all specimens of the incomplete type of pyloric gland metaplasia contained acid mucins and were further classified into two types: an incomplete type 1, which had Pg II but no Pg I activity, and an incomplete type 2, which had no Pg I or II activity.

Epithelium↗

PubMed1987

Placental glutathione S-transferase (GST-P) as a new marker for hepatocarcinogenesis: in vivo short-term screening for hepatocarcinogens.

Our laboratory has developed an in vivo short-term screening test for hepatocarcinogens based on quantitation of gamma-glutamyl transpeptidase (gamma-GT) positive foci. However, gamma-GT positive hepatocytes appear in periportal areas under a variety of circumstances apparently unrelated to hepatocarcinogenesis. Glutathione S-transferase placental type (GST-P), which is hardly detectable in normal rat liver, was recently demonstrated as a new marker protein for preneoplastic liver foci. In experiment I, rats were initially given a single dose (200 mg/kg) of diethylnitrosamine intraperitoneally and 2 weeks later were treated with test compounds for 6 weeks. All rats were subjected to partial hepatectomy at week 3. The long-term development of preneoplastic lesions was followed in rats for 50 weeks. The immunohistochemical investigation of GST-P binding and the histochemical demonstration of gamma-GT in serial sections revealed that almost all gamma-GT foci were GST-P positive, but 5-10% of GST-P foci could not be detected by gamma-GT staining. From week 8, many gamma-GT foci partially lost gamma-GT activity. However, no comparable disappearance of GST-P was evident in the lesions. All hepatocellular carcinomas (HC) found at week 50 consisted of GST-P positive HC cells. In contrast, 37.9% (11/29) of HC were negative for gamma-GT. In experiment II (in vivo short-term screening test for hepatocarcinogens), rats were treated in the same manner as for experiment I and killed at week 8. Fifty-eight chemicals were investigated for their potential to modify GST-P positive foci development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗