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T Sugimura

Publications and source records attributed to T Sugimura.

At least 397 records · Page 22Linked to original sources
PubMed1991

Evaluation of glycoprotein gII ISCOMs subunit vaccine for pseudorabies in pig.

One of the pseudorabies virus glycoproteins, gII, was integrated into Quil A matrix and formed an antigenic presentation structure known as immunostimulating complexes (ISCOMs). The gII ISCOMs protected mice from a lethal infection of pseudorabies virus (PrV). Subsequently, the efficacy of gII ISCOMs as a vaccine was evaluated in pigs, a natural host species of PrV. Immunization of pigs with gII ISCOMs protected them from PrV-induced acute symptoms and death. The serum obtained from immunized pigs was clearly discriminated from that of infected pigs by immunoprecipitation. The data indicated that the ISCOM technique was useful in PrV subunit vaccine preparation and demonstrated the importance of glycoprotein gII as a component of PrV vaccine.

Animals↗
PubMed1991

The formation of heart DNA adducts in F344 rat following dietary administration of heterocyclic amines.

Most heterocyclic amines formed during the cooking of meat and fish have been shown to form adducts in the livers of rats. Recently, however, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), administered in the diet to Fischer 344 (F344) rats for 4 weeks, was shown to produce the highest levels of adducts in the heart. In the present study 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 2-amino-6-methyldipyrido[1,2-a:1',2'-d]imidazole (Glu-P-1) were given to F344 rats at carcinogenic dose levels (IQ 0.03%, MeIQx 0.04%, Trp-P-1 0.015%, Glu-P-1 0.05%) in the diet for 4 weeks. DNA adducts in the liver and heart were analyzed by 32P-postlabeling. DNA adducts were demonstrated to appear in the hearts of all animals exposed to heterocyclic amines at the following levels: IQ, 1.8 adducts/10(7) nucleotides, MeIQx, 3.8/10(7) ntd, Trp-P-1, 20/10(7) ntd and Glu-P-1, 7.2/10(7) ntd. Values for the heart were 10-20% of the respective liver adduct levels. Heart adducts increased linearly throughout the observed period when MeIQx was administered for up to 40 weeks. When MeIQx feeding was discontinued after 20 weeks and the animals subsequently given the basal diet, the adduct level at 20 weeks did not change during the following 20 weeks. A possible role for heart DNA alterations caused by food-borne heterocyclic amines in the development of age-related myopathies and cardiovascular disease is not inconceivable.

Administration, Oral↗
PubMed1991

The effect of dose and enzyme inducers on the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats.

Male Fischer 344 rats were given a single dose of 0.03-30 mg/kg of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ([14C]PhIP), the radioactivity in urine and feces was determined over 48 h, and the major metabolites were identified and quantified. Dose had little effect on the profile of metabolites in the urine but did influence the profile in the feces. PhIP was more efficiently metabolized at higher doses. In addition, rats were pretreated with Aroclor 1254 (PCB), 3-methylcholanthrene (MC), phenobarbital (PB), PhIP and corn oil prior to a single dose of [14C]PhIP, and compared with a control group receiving [14C]PhIP only. The major metabolites in the urine and feces were quantitated for each group, as well as PhIP binding to serum proteins, hemoglobin and selected tissues. Pretreatment with MC and PCB resulted in an increase in the amount of 4'-hydroxylation of PhIP and a decrease in the amount of N-hydroxylated metabolites in the urine. Pretreatment with PB resulted in an increase in the amount of N-hydroxylated metabolites, but a decrease in 4'-hydroxylation. Pretreatment with either MC or PCB resulted in an increase in PhIP binding to the liver and kidney, while reducing the binding in other tissues. Animals pretreated with PhIP showed few significant differences from the untreated group, while pretreatment with PB in general resulted in a decrease of PhIP binding in tissues.

Animals↗
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

Fate and distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats.

Fischer 344 rats were given a single dose of 0.60 mg/animal of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by gavage; and radioactivity contained in feces, urine, blood, serum proteins, hemoglobin, and tissues was determined at 12, 24, 48 and 96 h after dosing. One major and four minor radioactivity-containing fractions were found in the urine and one major and two minor radioactivity-containing fractions were found in the feces. The feces was the major route of excretion, representing 78% of dose during the first 24 h, and unchanged PhIP in the feces accounted for 51% of the dose. Unmetabolized PhIP was also shown to be the major radioactive fraction in bile and feces from animals given a single dose by i.p. injection. Blood contained a small fraction of the dose and the major, persistently-bound form of PhIP in the blood was to hemoglobin. At 12 h after administration of the dose the colon and cecum contained the highest concentration of radioactivity, while at later times the kidney and liver showed the highest concentration. Of the tissue-contained radioactivity 80-90% was ethanol insoluble at time points later than 24 h, suggesting that it was covalently bound to macromolecules.

Animals↗
PubMed1991

L-arginine-dependent formation of N-nitrosamines by the cytosol of macrophages activated with lipopolysaccharide and interferon-gamma.

The cytosol fraction of J774-1 murine macrophages activated with lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) was found to nitrosate a wide range of secondary and tertiary amines. The reaction was dependent on L-arginine and NADPH. The optimal pH for nitrosation was 7.2-7.3. Nitrosation was inhibited by arginine derivatives such as NG-monomethyl-L-arginine and NG-nitro-L-arginine, well-known inhibitors of nitric oxide (NO) synthase. These results indicate that nitrosation is mediated by NO synthase, which catalyzes formation of NO and L-citrulline from L-arginine. Nitrosamine formation also required oxygen and was inversely correlated with the basicity of nitrosatable amines. The nitrosation was inhibited by oxyhemoglobin, an NO trapping agent, and enhanced by superoxide dismutase, which stabilizes NO. LPS + IFN-gamma induced approximately 500-600 times greater nitrosation activity than that of non-activated macrophages. Macrophages treated with LPS alone exhibited 3-4 times greater nitrosation activity than untreated macrophages, whereas macrophages treated with IFN-gamma alone did not show enhanced nitrosation activity. A combination of the cytosols from macrophages treated with LPS alone and IFN-gamma alone did not nitrosate morpholine as rapidly as the cytosol of macrophages treated with both compounds together. The activity for forming L-citrulline and nitrite/nitrate from L-arginine was markedly induced by treatment with either LPS alone or LPS + IFN-gamma but not with IFN-gamma. Those results suggest that some other factor(s) in addition to NO synthase is involved for efficient nitrosation by the macrophage cytosol. This factor(s) was not induced in macrophages by either LPS- or IFN-gamma alone, but was induced only in the presence of the two compounds.

Amino Acid Oxidoreductases↗
PubMed1991

Presence of carcinogenic heterocyclic amines in urine of healthy volunteers eating normal diet, but not of inpatients receiving parenteral alimentation.

For estimation of human exposures to carcinogenic heterocyclic amines, the amounts of four compounds, 3-amino-1, 4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), in human urine were measured. Twenty-four hour urine specimens were collected from ten healthy volunteers eating normal diet (five males and five females) and three inpatients (two males and a female) receiving parenteral alimentation, and the levels of the four heterocyclic amines were measured by HPLC after partial purification by treatment with blue cotton and ion exchange column chromatography. Trp-P-1, Trp-P-2, PhIP and MeIQx were detected in the 24 h urine samples of all healthy volunteers at levels of 0.04-1.43 ng, 0.03-0.68 ng, 0.12-1.97 ng and 11-47 ng respectively. As 1.8-4.9% of an oral dose of MeIQx is reported to be excreted unchanged in the urine, the daily exposure of humans to MeIQx was estimated to be 0.2-2.6 micrograms/person. The four heterocyclic amines were not detected in the urine of parenterally fed inpatients. These results indicate that humans are continually exposed to carcinogenic heterocyclic amines in food, and these compounds may not be formed endogenously.

Adolescent↗
PubMed1991

A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which is produced during cooking and is mutagenic to bacteria and cultured mammalian cells, was found to induce high incidences of colon and mammary carcinomas in F344 rats when administered at a concentration of 400 p.p.m. in the diet for 52 weeks. Since PhIP is the most abundant of the mutagenic heterocyclic amines in cooked meat and fish, the compound might be related to malignancies of the colon and breast in humans.

Animals↗
PubMed1991

Synergistic enhancement of glutathione S-transferase placental form-positive hepatic foci development in diethylnitrosamine-treated rats by combined administration of five heterocyclic amines at low doses.

Potential synergism among 5 heterocyclic amines at low doses in the induction of glutathione S-transferase placental form (GST-P)-positive liver cell foci was examined in an 8-week experiment using male rats initially given diethylnitrosamine (200 mg/kg, ip). The heterocyclic amines applied were 3-amino-1-methyl-5H-pyrido[4,3-b]indole (500 ppm), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole (500 ppm), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (800 ppm), 2-amino-9H-pyrido[2,3-b]indole (800 ppm), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, 400 ppm). Separate groups received each chemical at the dose used in earlier carcinogenicity assays (above doses), at 1/5 or 1/25 of these, or all 5 chemicals together, each at the 1/5 or 1/25 levels. The numbers and areas of GST-P-positive foci were significantly increased with all chemicals, except for PhIP, at the highest dose, the results being consistent with the reported liver carcinogenicity. In the combined treatment at the 1/5 dose levels, synergistic enhancement occurred; the numbers and areas of foci were significantly increased above the sums of individual data. However, this was not the case for the 1/25 dose groups. Although the synergism between pyrolysis products in liver carcinogenesis depended on the dose and combination of chemicals, the findings, together with those from a previous experiment using 5 different heterocyclic amines, are of particular significance since several heterocyclic amines might be simultaneously generated during cooking of foodstuffs.

Amines↗
PubMed1991

Induction of aberrant crypt foci in the large intestine of F344 rats by oral administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to rat colon was investigated using the appearance of colonic aberrant crypt (AC), a preneoplastic lesion, as a marker. The number of AC foci per colon at experimental week 4 was 1.3 +/- 0.8; almost half the level of AC foci induced by 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), which is a known colon carcinogen. No ACs were observed in rats of the control group. A repeat experiment showed that induction of AC foci by PhIP administration was reproducible and a significant increase in the number of AC foci, 3.0 +/- 0.0, was observed after 12 weeks of PhIP administration. The majority of ACs induced by PhIP were localized in the distal part of the colon. The distribution was similar to those induced by Glu-P-1 and 1,2-dimethylhydrazine. Those data suggested that PhIP is possibly carcinogenic to rat colon.

1,2-Dimethylhydrazine↗
PubMed1991

Induction of intestinal adenocarcinomas by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Nagase analbuminemic rats.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine in cooked foods, was examined for carcinogenic potential using Nagase analbuminemic rats (NARs), which are sensitive to various carcinogens. The concentration of PhIP in the diet was 0.04% at the beginning of the experiment, this being subsequently gradually reduced to 0.01% to avoid severe body weight loss. Ten of 13 treated NARs developed a total of 36 intestinal tumors within the 311-day experimental period. Among these, 22 were adenocarcinomas and 2 were adenomas of the small intestine, 4 were adenocarcinomas of the cecum and 8 were adenocarcinomas of the large intestine. The results suggest that PhIP could represent a significant risk to human populations exposed to foods containing heterocyclic amines.

Adenocarcinoma↗
PubMed1991

Inhibitory effect of 2-O-octadecylascorbic acid in agglutination assay with concanavalin A; short-term examination of rat urinary bladder carcinogenesis.

A derivative of ascorbic acid, 2-O-octadecylascorbic acid (CV-3611), is a strong scavenger of active oxygen species. We examined the effect of CV-3611 on a short-term test of bladder carcinogenesis, using concanavalin A (Con A)-dependent agglutination of isolated bladder epithelial cells. Rats were given 0.01% N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN) for 1 week, and then 5% sodium saccharin or 2% DL-tryptophan or 0.01% BHBN alone or with 0.002, 0.006 or 0.02% CV-3611 for 3 weeks. Treatment with CV-3611 reduced the effects of the bladder tumor promoters sodium saccharin and DL-tryptophan by 48-86 and 65-87%, respectively. CV-3611 also reduced the number of aggregates of bladder epithelial cells from rats treated with BHBN for 4 weeks. These results suggest that CV-3611 has a suppressive effect on rat bladder carcinogenesis.

Agglutination Tests↗
PubMed1991

Ki-ras activation in pancreatic carcinomas of Syrian hamsters induced by N-nitrosobis(2-hydroxypropyl)amine.

Five pancreatic carcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in Syrian golden hamsters were analyzed for activation of Ki-ras at codons 12 and 13, using the polymerase chain reaction and direct sequencing. The Ki-ras gene was shown to be activated in four of the five carcinomas, and the results were further confirmed by subcloning and sequencing. All the mutations involved a G-to-A transition at the second position of codon 12, which resulted in a change at the amino acid level from glycine to aspartic acid. This mutation is identical with that reported for pancreatic tumors of Syrian hamsters induced by N-nitrosobis(2-oxopropyl)amine.

Animals↗
PubMed1991

Purification and characterization of human papillomavirus type 16 E7 protein with preferential binding capacity to the underphosphorylated form of retinoblastoma gene product.

Human papillomavirus type 16 E7 is considered to be a major viral oncoprotein playing an important role(s) in cervical cancers. E7 protein was shown to bind to the protein product of the retinoblastoma gene (RB), while simian virus 40 large T and adenovirus E1A were also shown to possess binding activity to RB protein. The RB protein is a cell cycle regulator that is highly phosphorylated specifically in S, G2, and M, whereas it is underphosphorylated in G0 and G1. Recently, large T was demonstrated to bind preferentially to the underphosphorylated RB protein, which is considered to be an active form restricting cell proliferation. However, it is not known whether E7 can bind to phosphorylated RB protein. We successfully purified large quantities of unfused human papillomavirus type 16 E7 protein expressed in Escherichia coli by using a T7 promoter-T7 RNA polymerase system. The purified E7 protein was demonstrated to bind preferentially to the underphosphorylated RB protein.

Amino Acid Sequence↗
PubMed1991

Isolation and structural determination of a mutagenic substance in creatine pyrolysate.

The pyrolysis product of creatine showed potent mutagenic activity to Salmonella typhimurium TA98 with metabolic activation by S9 mix. One of the mutagenic substances in creatine pyrolysate was isolated and named Cre-P-1. Its structure was determined by X-ray crystallography to be 4-amino-1,6-dimethyl-2-methylamino-1H,6H-pyrrolo[3,4-f]benzimidazole- 5,7-dione. Cre-P-1 is the first registered mutagenic heterocyclic amine containing oxygen atoms in the molecule, that has been isolated from pyrolysis products.

Animals↗
PubMed1991

Chromosomal localization of putative tumor-suppressor genes in several human cancers.

Restriction-fragment-length polymorphism analysis was performed on several different types of human cancers, including carcinoma of the uterine cervix, neuroblastoma, hepatocellular carcinoma, pheochromocytoma, stomach cancer, and small-cell lung carcinoma (SCLC), to determine the chromosomal loci of putative tumor-suppressor genes in each type of tumor because less of heterozygosity (LOH) is supposed to unmask the recessive mutation of tumor-suppressor gene in the remaining allele. Chromosomal loci showing frequent LOH differed among these tumors, suggesting that there are several tumor-suppressor genes in the human genome and that critical genes for the development of each type of tumor are different. In some cases LOH was observed in the early stage of tumor such as chromosome 3p loss in carcinoma of the uterine cervix, and in other cases it was observed only in the advanced stage of tumor such as chromosomes 4 and 16q loss in hepatocellular carcinoma. These results suggest that there are two different types of tumor-suppressor genes: one is the gene whose inactivation is responsible for malignant transformation of a normal cell and the other is the gene whose inactivation is responsible for the progression of a tumor cell. In SCLC, LOH at three different chromosomal loci, 3p, 13q, and 17p, was simultaneously observed in nearly 100% of tumors. It was observed even in stage I tumors and an untreated tumor, and it occurred prior to N-myc amplification. These results may imply that at least six genetic alterations are necessary to convert a normal cell into a fully malignant cancer cell in SCLC.

Alleles↗
PubMed1991

Loss of amplified genes by poly(ADP-ribose) polymerase inhibitors.

A poly(ADP-ribose) polymerase inhibitor, benzamide (BA), was found to induce flat revertants of NIH 3T3 cells that had been transformed by human Ha-ras, rat Ki-ras, rat c-raf, and human ret-II. These genes had been amplified in original transformants, but they were completely eliminated by BA. Contrary to this, endogenous activated Ha-ras in a human bladder carcinoma cell line, T24, was not eliminated by BA. The gene loss seemed to be restricted to exogenous and/or amplified sequences. BA also eliminated the amplified c-myc gene in HL-60 cells, concomitant with differentiation into granulocytes. We demonstrated that the amplified c-myc gene was not present as episomes. It is probably present as double minutes or a homogeneously staining region. Dimethylsulfoxide also induced differentiation at a concentration that did not inhibit poly(ADP-ribose) polymerase. The cell lost the c-myc gene in association with this differentiation. The amplified c-myc gene in a colon adenocarcinoma cell line, COLO 320HSR, and the amplified mdr-1 gene in an adriamycin-resistant myelogenous leukemia cell line, K562/ADM, were not eliminated by BA. Various poly(ADP-ribose) polymerase inhibitors also eliminated human Ha-ras in the NIH 3T3 transformant and the c-myc gene in HL-60 cells.

3T3 Cells↗