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S Fukushima

Publications and source records attributed to S Fukushima.

At least 289 records · Page 16Linked to original sources
PubMed1991

L-ascorbic acid amplification of bladder carcinogenesis promotion by K2CO3.

The dose dependence of K2CO3 promotion of two-stage urinary bladder carcinogenesis and the amplifying effects of additional L-ascorbic acid (AsA) administration were investigated. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then fed basal diet containing K2CO3 at levels of 0, 1, 1.5, 2.2, and 3% with or without 5% AsA or 3% NaHCO3 supplementation from weeks 5 to 8 (4 weeks) and weeks 12 to 20 (9 weeks). During weeks 9 to 11 (3 weeks), the rats were fed 3% uracil in their diet. For controls, rats without N-butyl-N-(4-hydroxybutyl)nitrosamine treatment were given either 3% K2CO3, 5% AsA, or both plus the uracil treatment. The total observation period was 20 weeks. K2CO3 dose dependently increased the numbers of the putative preneoplastic lesion, papillary or nodular hyperplasia, and papillomas in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine. AsA (5%), while itself exerting no promoting effect, amplified the enhancing influence of K2CO3 on the induction of papillary or nodular hyperplasia and papillomas. The dose-dependent elevation of urinary pH and K+ concentration was associated with K2CO3 treatment with or without AsA. Thus, increased urinary pH and K+ concentration appear to play important roles in K2CO3 promotion, and AsA amplifies this promotion.

Animals↗
PubMed1991

Simultaneous determination of testosterone and androstadienone (sex attractant) in human plasma by gas chromatography-mass spectrometry with high-resolution selected-ion monitoring.

Androsta-4,16-dien-3-one (androstadienone) and androst-4-en-3-one-17 beta-ol (testosterone) in healthy human plasma were simultaneously determined under several experimental conditions by gas chromatography-mass spectrometry with high-resolution selected-ion monitoring. Internal standards were [2,2,4,6,6-2H5]androstadienone and [2,2,4,6,6-2H5]testosterone. Samples were extracted with an Extrelut column, purified using Lipidex 5000 and converted into hydroxime-trimethylsilyl derivatives for determination. Physiological concentrations of androstadienone and testosterone found in eleven healthy men were 2.05 +/- 0.74 and 18.6 +/- 4.9 pmol/ml in plasma (mean +/- S.D.), respectively. No correlation was observed between these steroid concentrations.

Adult↗
PubMed1991

Molecular cloning of human epidermal transglutaminase cDNA from keratinocytes in culture.

We have isolated a cDNA encoding human epidermal transglutaminase, a key enzyme of terminal differentiation of keratinocytes. A cDNA library from cultured human keratinocytes was screened by a PCR-amplified partial cDNA fragment of the enzyme with oligonucleotide primers based on the homology of the transglutaminase family. The cDNA is 2734 bp coding a protein of 817 amino acids. The several regions including the active site cysteine residue are highly conserved among the transglutaminase family. However, the charged N-terminal domain is unique to the epidermal transglutaminse, suggesting that the region is involved in the function of the enzyme in keratinocytes.

Amino Acid Sequence↗
PubMed1991

Effects of phenolic antioxidants in low dose combination on forestomach carcinogenesis in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine.

The combined effects of low doses of promoters or carcinogens on two-stage forestomach carcinogenesis were examined in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine. Groups of 15 rats were given a single 150 mg/kg body weight intragastric dose of N-methyl-N'-nitro-N-nitrosoguanidine. Starting 1 week later they were fed a diet containing low doses of known forestomach promoters/carcinogens (0.5% caffeic acid, 0.2% catechol, 0.5% butylated hydroxyanisole, or 0.25% 2-tert-butyl-4-methylphenol), alone or in combination, or basal diet without antioxidant supplement for 35 weeks. Histopathological examination revealed the incidences of forestomach squamous cell carcinomas in animals treated with N-methyl-N'-nitro-N-nitrosoguanidine followed by caffeic acid, catechol, butylated hydroxyanisole, 2-tert-butyl-4-methylphenol, and basal diet to be 27, 20, 13, 13, and 7%, respectively, whereas the incidence increased to 80% by the combined treatment with these four chemicals. The present results thus show that although the low doses of individual promoters/carcinogens did not have significant promoting activity, their combination exerted a strong enhancing influence on rat forestomach carcinogenesis. The findings indicate the importance of summation and synergism at a low dose for agents present in the human environment.

Animals↗
PubMed1991

Comparative promoting activities of phosphate salts on rat two-stage bladder carcinogenesis under conditions of equivalent urinary Na+ or K+ levels.

Promoting effects of Na or K phosphate salts on rat two-stage bladder carcinogenesis were compared. Animals were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and thereafter received 1.4% Na3PO4, 2.0% NaH2PO4, 1.0% K3PO4, or 2.5% KH2PO4, these dietary concentrations being selected because they result in approximately equal levels of Na+ and K+ in the urine, equivalent to moderate natriuresis or kaluresis in comparison with our previous data. Treatment with Na3PO4 or K3PO4 induced significant increase in urinary pH compared with control values, whereas urinary pH in the NaH2PO4 and KH2PO4 groups was comparable to control values. With regard to preneoplastic lesion development, both incidences and multiplicity were significantly increased in the groups given Na3PO4 or K3PO4 compared with both controls and NaH2PO4 or KH2PO4 groups, respectively. Furthermore, treatment with Na3PO4 significantly increased multiplicity of papillomas, accompanied by a tendency to increased incidence. No statistically significant difference in promoting potential between Na3PO4 and K3PO4 groups was evident. The present results thus suggest that tumor promotion under conditions of moderate natriuresis or kaluresis depends primarily on high urinary pH.

Animals↗
PubMed1991

DNA synthesis and scanning electron microscopic lesions in renal pelvic epithelium of rats treated with bladder cancer promoters.

The proliferation response of rat renal pelvic epithelium, lined by transitional epithelium, to administration of various bladder cancer promoters was investigated. In addition, prostaglandin E2 (PGE2), lipid peroxide (LPO), malondialdehyde (MDA) and cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels were assessed in urine of rats given the non-promoter L-ascorbic acid (AsA) and the promoters sodium L-ascorbate (AsA-Na) or sodium bicarbonate (NaHCO3) for 4 or 8 weeks. DNA synthesis in the renal pelvic epithelium, as assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation, was increased in the groups given AsA-Na, an extremely high dose of sodium chloride (NaCl), tert-butylhydroquinone (TBHQ) or ethoxyquin (EQ). Moreover, with the exception of AsA-Na, all treatments that induced an elevation of DNA synthesis also caused morphological epithelial alterations as observed by scanning electron microscopy (SEM). Treatment with butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) did not result in any proliferative response of the rat renal pelvis. No treatment-related changes in urinary PGE2 and cyclic AMP were noted, although AsA-Na and AsA but not NaHCO3 reduced levels of LPO and MDA in the urine. The results indicate that while the response of renal pelvic epithelium to certain bladder cancer promoters is similar to that of the bladder itself, none of the urinary cellular growth or free radical biochemical parameters is directly related to urothelial cell proliferation.

Animals↗
PubMed1991

Uracil-induced calculi and carcinogenesis in the urinary bladder of rats treated simultaneously with N-butyl-N-(4-hydroxybutyl)nitrosamine.

Urinary bladder carcinogenicity of uracil and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in combination was investigated in male F344 rats. Two experiments were performed: in the first animals were treated with 3.0, 1.0 and 0.3% uracil in the diet and/or 0.005% BBN in the drinking water for 36 weeks followed by a 4 week period without chemicals, the total observation time being 40 weeks; in the second rats received 3.0% uracil in the diet or 0.05% BBN in the drinking water for 4 weeks. In the first experiment, a markedly high incidence of carcinomas was observed in the urinary bladder with both 3.0% uracil alone (11/15, 73%) and 3.0% uracil plus 0.005% BBN (18/20, 90%) treatments. The multiplicity, i.e. numbers of carcinomas induced per 10 cm of basement membrane, was significantly higher with the latter treatment (P less than 0.05), as were proliferative lesions in the renal pelvis. Stone formation was observed in all 3.0% uracil treatment animals. In the second experiment, prostaglandin E2 levels in bladder tissue of uracil-treated animals proved to be significantly higher than in BBN-treated or untreated animals. Thus, the results clearly indicated that calculi associated with 3.0% uracil ingestion can themselves cause carcinoma development in the urinary bladder, while also acting as a potent co-carcinogen agent for BBN carcinogenesis.

Animals↗
PubMed1991

Modifying effects of the naturally occurring antioxidants gamma-oryzanol, phytic acid, tannic acid and n-tritriacontane-16, 18-dione in a rat wide-spectrum organ carcinogenesis model.

The modifying effects of the naturally occurring antioxidants gamma-oryzanol, phytic acid, tannic acid and n-tritriacontane-16, 18-dione (TTAD) were investigated in a rat wide-spectrum organ carcinogenesis model. Animals were initiated with two i.p. injections of 1000 mg/kg body wt 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) followed by two i.g. administrations of 1500 mg/kg body wt N-ethyl-N-hydroxy-ethylnitrosamine (EHEN), and then three s.c. injections of 75 mg/kg body wt 3,2'-dimethyl-4-aminobiphenyl (DMAB) during the first 3 weeks. Starting 1 week after the last injection, groups of rats received diet containing 1% gamma-oryzanol, 2% phytic acid, 0.2% TTAD or 1% tannic acid or basal diet alone for 32 weeks. Animals were then killed and complete autopsy was performed at the end of week 36. Histological examination revealed enhancement of lung carcinogenesis by gamma-oryzanol, and the incidence of urinary bladder papillomas to be increased by phytic acid. On the other hand, TTAD inhibited hepatic and pancreatic carcinogenesis. Phytic acid and tannic acid were marginally effective in inhibiting hepatic and colon carcinogenesis respectively. The results thus indicated that naturally occurring antioxidants each exert specific modifying effects depending on the organ site and indicate that wide-spectrum carcinogenesis models are useful for defining complex influences.

Adenoma↗
PubMed1991

Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses.

Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.

Animals↗
PubMed1991

Selective induction of rat urinary bladder tumors by simultaneous administration of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and butylated hydroxyanisole or butylated hydroxytoluene is associated with increased DMAB-DNA adduct formation.

Modification of 3,2'-dimethyl-4-aminobiphenyl (DMAB) multi-organ carcinogenesis by simultaneous treatment with butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) was studied using young and old male F344 rats. Animals, 4 or 54 weeks old, were given DMAB (s.c. injection of 50 mg/kg body wt once a week for 10 weeks) along with BHA (2.0% in diet for 11 weeks) or BHT (1.0% in diet for 11 weeks). The experiments were terminated 55 weeks after the commencement. Combined administration of BHA or BHT with the carcinogen resulted in development of urinary bladder tumors in greater than 90% of both young and old rats thus treated, whereas no tumors were induced in animals given DMAB alone. In contrast, the appearance of preneoplastic lesions in the liver and pancreas was reduced by BHA or BHT treatment. Tumor development (less than 30% incidence) was also evident in the small and large intestines, prostate, preputial glands, skin/subcutis and ear duct, with no modification by BHA or BHT. No ageing effects were evident. The formations of DMAB-DNA adducts, evaluated by the enzyme-linked immunosorbent assay and immunohistochemical staining, correlated well with tumorigenesis in the urinary bladder, liver and pancreas. The selective enhancement of urinary bladder tumor induction by BHA and BHT appeared to be due to both increased DMAB-DNA adduct formation caused by metabolic alteration of DMAB in the liver and increased DNA synthesis in the urothelial cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Timing effects of uracil-induced urolithiasis on amplification of second-stage promotion in rat bladder carcinogenesis.

The post-initiation enhancing activities of the non-genotoxic agent NaHCO3 and the genotoxic agent N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) in combination with uracil-induced urolithiasis were investigated in a rat bladder carcinogenesis model. Animals were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks, and then 3% uracil was given for 3 weeks in the early (weeks 4-7), middle (weeks 8-11) or late (weeks 12-15) post-initiation phase. In addition, administration of 3% NaHCO3, 20 ppm EHBN or no chemical supplement was performed for the 13 weeks when the rats were not receiving BBN or uracil. NaHCO3 in sequential combination with early and middle stages uracil treatment strongly enhanced tumorigenesis in the urinary bladder, while EHBN treatment amplified lesion development at the middle stage only of uracil treatment. DNA synthesis and associated epithelial surface alterations observed by scanning electron microscopy tended to be increased in the NaHCO3 and EHBN groups without BBN initiation, independently of uracil treatment timing. The present results demonstrated that uracil-induced urolithiasis during the middle post-initiation phase is highly active in enhancing bladder tumor development under the influence of a promoter or carcinogen.

Animals↗
PubMed1991

Summation effects of uracil and other promoters on epithelial lesion development in the F344 rat urinary bladder initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Five non-genotoxic chemicals previously demonstrated to be bladder cancer promoters in 36-week in vivo assays for carcinogenesis were reevaluated in a 20-week experiment in order to assess the summation influence of dietary uracil, a component of RNA, on the development of (pre)neoplastic lesions. The test chemicals, sodium bicarbonate, sodium L-ascorbate, sodium citrate, butylated hydroxytoluene and ethoxyquin, were mixed into the diet at concentrations of 3%, 5%, 5%, 1% and 0.8%, respectively, and administered to male F344 rats after initiation with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks. The test chemicals were given from the 4th to the 8th and the 11th to 20th experimental weeks, uracil being administered at the level of 3% in the diet during the intervening period. Rats in the control group received only BBN and uracil. All animals were killed at week 20 and the bladders were evaluated for the occurrence of putative preneoplastic papillary or nodular (PN) hyperplasia and tumors. Significant increase in the occurrence of PN hyperplasia was observed in all groups initiated with BBN and fed uracil and test chemicals. Quantitative values for papillomas were also significantly increased except in the ethoxyquin-treated group. The results confirm that uracil given in the middle of the post-initiation stage enhances the promoting activity of chemicals and suggest that the use of this chemical might be useful to reduce the duration of current bioassays for bladder chemical carcinogens.

Animals↗
PubMed1991

Renal pelvic carcinoma which shows metastatic potential to distant organs, induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in NON/Shi mice.

Renal pelvic carcinoma was induced in mice by giving N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Initially, differences in renal pelvic carcinogenesis by BBN were examined in three male mouse strains: NON/Shi, which demonstrate spontaneous hydronephrosis with incidences of 10-30%, and DS/Shi and B6C3F1, which do not exhibit hydronephrosis. When mice of these strains were given 0.05% BBN in the drinking water for 12 weeks followed by water without BBN for 8 weeks, renal pelvic carcinoma morphologically similar to human carcinomas developed in 8 of 23 NON/Shi mice (35%). Metastasis to the lung was found in one of them (13%). B6C3F1 and DS/Shi mice had no pelvic tumors, but the response to urinary bladder carcinogenesis in NON/Shi mice was nearly equal to that in DS/Shi and B6C3F1 mice. These results suggest that renal pelvic carcinogenesis is related to the presence of stagnant urine containing carcinogen in the renal pelvis. In a second experiment, we examined renal pelvic carcinogenesis in NON/Shi mice given BBN for 4 weeks followed by water without BBN for 32 weeks. The incidence of renal pelvic carcinoma (28%) was similar to that in the first experiment, but the incidence of metastasis was markedly elevated to 60%. These results indicate that BBN treatment can induce renal pelvic carcinoma which often metastasizes to the lung in NON/Shi mice.

Abdominal Neoplasms↗
PubMed1991

Modifying effects of various chemicals on preneoplastic and neoplastic lesion development in a wide-spectrum organ carcinogenesis model using F344 rats.

Modifying potentials of various chemicals on tumor development were investigated in a wide-spectrum organ carcinogenesis model using male F344/DuCrj rats. The animals were treated with N-nitrosodiethylamine (100 mg/kg body weight, ip, single injection at the commencement of the study), N-methyl-N-nitrosourea (20 mg/kg body weight, ip, 4 times during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in drinking water, during weeks 3 and 4) for multi-organ initiation and then were given one of 14 test chemicals including 6 hepatocarcinogens, 7 non-hepatocarcinogens and 1 non-carcinogen, or basal diet for 16 weeks. All rats were killed at the end of week 20, and the major organs were carefully examined for preneoplastic and neoplastic lesions. Immunohistochemical demonstration of glutathione S-transferase-positive foci was also used for quantitative assessment of liver preneoplastic lesion development. Modifying effects were shown for 11 out of 14 test agents in the liver, forestomach, glandular stomach, lung, urinary bladder or thyroid, 7 of them targeting more than two organs. This was the first demonstration to our knowledge that clofibrate possesses enhancing potential for urinary bladder carcinogenesis and an inhibiting effect on thyroid carcinogenesis. Caprolactam showed no effect in any organ, in agreement with its established inactivity. The results indicated that the system could be reliably applied as a medium-term multiple organ bioassay for assessment of the modification potential of test agents in unknown target sites.

Administration, Oral↗
PubMed1991

Time- and dose-dependent induction of invasive urinary bladder cancers by N-ethyl-N-(4-hydroxybutyl)nitrosamine in B6C3F1 mice.

A sequential investigation of N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) bladder carcinogenesis was performed in male B6C3F1 mice maintained ad libitum on tap water containing 0.025% EHBN for 4, 12, 20, 28 and 36 weeks. A total of 81 invasive tumors, comprising 55 squamous cell carcinomas (SCCs) (68%), 25 transitional cell carcinomas (TCCs) (31%) and 1 adenocarcinoma (1%) were found. Of these, 23 (22 SCCs and 1 TCC) demonstrated invasion to the prostate, 3 metastasized to the lung, and 2 spread by peritoneal seeding. The anaplastic grade and extent of invasion of the SCCs significantly exceeded those of the TCCs. The results suggested a histogenetic pathway from simple dysplasia through papillary or nodular dysplasia and/or carcinoma in situ to eventual development of invasive carcinomas.

Animals↗
PubMed1991

Sex differences in o-phenylphenol and sodium o-phenylphenate rat urinary bladder carcinogenesis: urinary metabolites and electrolytes under conditions of aciduria and alkalinuria.

F344 male and female rats were administered 1.25% o-phenylphenol (OPP) or 2% sodium o-phenylphenate (Na-OPP) in combination with 3% NaHCO3 or 1% NH4Cl for 8 weeks and changes in the urinary bladder histopathology and the urinary components were examined. Administration of OPP with NaHCO3 resulted in marked urothelial hyperplasia in the urinary bladder of male rats, the response being less pronounced in females. OPP alone exerted no proliferative effect and NaHCO3 induced only slight hyperplasia in males. Na-OPP alone induced mild hyperplastic lesions only in males, this being completely prevented by concomitant administration of NH4Cl. The findings thus demonstrated a clear correlation between hyperplastic response and reported carcinogenic potential of these treatments. Of the urinary factors examined, increases in levels of pH and sodium ion concentration were positively associated with proliferative lesions especially in males, although the findings failed to explain the sex difference. Urinary concentrations of non-conjugated forms of OPP metabolites were also not directly correlated with the development of hyperplasias. Thus, changes in individual urinary factors presumably affect urothelial proliferation in combination rather than separately. The presence of OPP metabolites, including 2-phenyl-1,4-benzoquinone, in the urine may be unimportant in the OPP urinary carcinogenesis even under conditions of alkalinuria and high sodium ion concentration.

Ammonium Chloride↗
PubMed1991

Organ-specific modification of tumor development by low-dose combinations of agents in a rat wide-spectrum carcinogenesis model.

The combined effects of low doses of various carcinogens and carcinogenesis modifiers on tumor development were investigated by using a wide-spectrum organ carcinogenesis model in F344 rats. These agents were administered as three groups: (1) a group of known hepatocarcinogens; (2) a group of nitroso compounds having various target organ specificities; and (3) a group of antioxidants having various inhibiting or enhancing activities depending on the target organ. Doses were used which were generally below the known effective level for the individual chemical. These groups of chemicals were administered with or without prior administration of N-diethylnitrosamine (100 mg/kg body wt., i.p.), N-methylnitrosourea (4 x 20 mg/kg body wt., i.p.) and dihydroxy-di-N-propylnitrosamine (0.1% in drinking water for 2 weeks). The hepatocarcinogen group in combination with various nitroso compounds increased the incidences of liver hyperplastic nodules and hepatocellular carcinomas. In contrast, incidences were clearly reduced when the hepatocarcinogens and/or the nitroso compounds were administered in combination with the antioxidants. For the urinary bladder, the combination with nitroso compounds and antioxidants enhanced cancer development, and the addition of hepatocarcinogens further increased tumorigenesis. For the glandular stomach, additive effects on the numbers of pepsinogen isozyme 1-altered pyloric glands, a putative preneoplastic lesion, were produced by the combination treatment of antioxidants and the nitroso compounds. No synergistic effects on tumor development were seen in other organs. The results of the present study demonstrated that combinations of various compounds at low doses can additively or synergistically exert either enhancing or inhibitory effects on the development of preneoplastic and neoplastic lesions in different organs in a single model having a wide spectrum of organ effects.

Animals↗