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T Sugimura

Publications and source records attributed to T Sugimura.

At least 289 records · Page 16Linked to original sources
PubMed1994

Tissue-specific mutational spectra of 2-amino-3,4-dimethylimidazo[4,5-f]quinoline in the liver and bone marrow of lacI transgenic mice.

2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) is a food-borne heterocyclic amine, so clarification of its mutational spectrum is important for evaluation of its carcinogenic risk to humans. The mutational spectrum of MeIQ was investigated in the liver and bone marrow of transgenic mice carrying the lacI gene. By PCR--single-strand conformation polymorphism analysis and sequencing of the lacI gene, 81 and 61 mutations were identified in 80 and 59 mutants obtained from the liver and bone marrow respectively of three transgenic mice given food containing 300 p.p.m. MeIQ. In the liver, G-->T transversions were the most frequent, accounting for 46% of the total mutations, followed by G-->A transitions (25%). In the bone marrow, four types of mutations, G-->T transversions, G-->A transitions, complex mutations and one base deletions, each accounted for 21-23% of the total mutations. Of the total mutations, 10% were found at nucleotide 92 in the liver and at nucleotide 222 in the bone marrow. Analysis of 27 and 13 mutants from the liver and bone marrow respectively of control mice showed frequent G-->A transitions at CpG sites. These findings suggest a tissue-specific mechanism of mutagenesis.

Animals↗
PubMed1994

Synergistic enhancement of hepatic foci development by combined treatment of rats with 10 heterocyclic amines at low doses.

Potential synergism between 10 carcinogenic heterocyclic amines [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-6 methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-amino-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C), 2-amino-9H-pyrido[2,3-b]indole (A alpha C) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)] in rat liver carcinogenesis was examined. Male F344 rats were initially given diethylnitrosamine (200 mg/kg, i.p.) and beginning 2 weeks later received heterocyclic amines individually at doses 1/10 of that proven to be carcinogenic or in combination at 1/10 or 1/100 doses for 6 weeks. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. The induction of immunohistochemically demonstrable placental glutathione S-transferase positive foci was significantly increased in rats given all 10 chemicals in combination at the 1/10 dose level while values were almost the same as in controls with the 1/100 dose mixture and the individual chemicals, except for Glu-P-1 which significantly increased foci development and Glu-P-2 and A alpha c which significantly decreased levels of foci at the 1/10 dose level. Thus apparent synergism was observed with the 1/10 dose level combination. When the data are considered together with our previous results obtained with five heterocyclic amines using 1/1, 1/5 and 1/25 dose levels, combined effects were found to be related to the number of chemicals included and the dose levels of each, with a possible isoadditive influence being common. The findings are of particular significance since heterocyclic amines and other carcinogenic agents might be simultaneously generated during cooking.

Amines↗
PubMed1994

Structural determination of a new mutagenic heterocyclic amine, 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx), present in beef extract.

We previously found two new mutagens, compounds I and II, in bacteriological-grade beef extract by monitoring the mutagenicity to a new Salmonella strain, YG1024; compound I was identified as 2-amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline (4-CH2OH-8-MeIQx). In the present study, we isolated compound II from the beef extract, which accounted for 2% of the total mutagenicity of materials adsorbed on blue cotton. Further, we found that a large quantity of compound II was produced by heating a mixture of creatine, threonine and glucose (1:1:0.5) at 200 degrees C for 5 h, the level being 860-fold of that in the beef extract. The structure of this compound was determined to be 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx) by X-ray crystallography. The amount of 7,9-DiMeIgQx in bacteriological-grade beef extract was estimated to be 53 ng/g. This compound induced 13 800 and 670 revertants of S. typhimurium YG1024 and TA98 respectively, per micrograms in the presence of S9 mix.

Animals↗
PubMed1994

Identification of N-(deoxyguanosin-8-yl)-2-amino-3,4-dimethylimidazo[4,5-f]quinoline (dG-C8-MeIQ) as a major adduct formed by MeIQ with nucleotides in vitro with DNA in vivo.

The N-hydroxylamine of a carcinogenic heterocyclic amine, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), was reacted with four 2'-deoxynucleoside 3'-monophosphates after O-acetylation. 32P-Postlabeling analysis demonstrated that the adduct was formed with only the guanine nucleotide, and the structure of the compound in the obtained adduct spot was determined to be N-(deoxyguanosin-8-yl)-MeIQ 3',5'-diphosphate (3',5'-pdGp-C8-MeIQ). DNA samples from livers of mice fed MeIQ were also 32P labeled under standard conditions and additionally treated with nuclease P1 and phosphodiesterase I. A single adduct spot was obtained and the structure of the adduct was identified as 5'-pdG-C8-MeIQ. Thus, MeIQ binds at the C-8 position of guanine in vitro and in vivo, like other heterocyclic amines.

Animals↗
PubMed1994

Carcinogenicity of a mutagenic compound from food, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C), in male F344 rats.

Carcinogenicity of 2-amino-3-methyl-9H-pyrido[2,3-b]-indole (MeA alpha C) was investigated at dietary levels of 0 (control), 0.01, 0.02, 0.04 and 0.08% using male F344/DuCrj rats. The administration of MeA alpha C was continued for 100 experimental weeks for the control, 0.01 and 0.02% groups, but halted after 52 and 26 experimental weeks for the 0.04 and 0.08% groups respectively due to severe toxicity. Well-differentiated hepatocellular carcinomas, lacking in control animals, were induced in 5/20 rats (25%) and 6/20 rats (30%) of the 0.01% and 0.02% groups respectively. Pancreatic acinar cell adenomas were also significantly increased in the 0.01% (30%) and 0.02% (40%) groups, in association with high incidences of hyperplastic lesions of acinar cells. Fibromas in the subcutis developed at a high incidence (70%) in the 0.02% group. MeA alpha C was also suggested to elicit fibrosarcomas in the salivary gland and transitional cell carcinomas in the urinary bladder. Among the non-neoplastic lesions, severe atrophy of the salivary glands and pancreas and severe renal toxicity were noteworthy. In conclusion, MeA alpha C is a multi-targeting carcinogen in rats, similar in this respect to other heterocyclic amines.

Alanine Transaminase↗
PubMed1994

Detection of guanine-C8-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine adduct as a single spot on thin-layer chromatography by modification of the 32P-postlabeling method.

N-(Deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (dG-C8-PhIP) has been shown to be a major adduct in DNA of rats given [3H]PhIP. However, when DNA from organs of rats fed PhIP was analyzed by the 32P-postlabeling method under standard and adduct-intensification conditions, four adduct spots were observed, and 3',5'-pdGp-C8-PhIP was detected as a minor, not a major, adduct spot. Since the three other major adduct spots were suspected to be those of adducted di- or oligo-nucleotides, the 32P-labeled samples were further treated with nuclease P1 and phosphodiesterase I and found to yield only a single adduct spot. The material in this adduct spot was confirmed to be 5'-pdG-C8-PhIP. Thus, using this newly modified 32P-postlabeling method, dG-C8-PhIP was detected as a major adduct in DNA of rats given PhIP.

Animals↗
PubMed1994

Presence of p53 mutations in 3Y1-B clone 1-6: a rat cell line widely used as a normal immortalized fibroblast.

The 3Y1 cell line, established from a rat whole embryo, is widely used as a normal immortalized fibroblast. We analyzed p53 mutations in four clonal lines derived from the 3Y1 cell line; 3Y1-B clone 1-6, 3Y1-C and two clonal lines (3Y1 cl-3 and 3Y1 cl-6) which had been transformed by the human papilloma virus E6 gene. Polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis and DNA sequencing showed that three clonal lines had a double mutation at codons 130 and 136 on the same allele and that the other clonal line, 3Y1 cl-3, had no mutations. 3Y1-B clone 1-6, which has been registered as the standard clonal line at the Japanese Cancer Research Resources Bank, demonstrated weak bands of the wild type allele, suggesting the existence of heterogeneous cell types in this "clonal" line. PCR-SSCP analysis of 25 subclones obtained by limiting dilution of 3Y1-B clone 1-6 cells revealed a mixture of two types of cells; 12 subclones showed only the bands of mutated allele, and 13 subclones showed both bands of the wild and mutated p53 alleles. These findings should be taken into consideration when using this cell line as a normal immortalized cell line.

Animals↗
PubMed1994

p53 gene mutation in hepatocellular carcinoma induced by 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates.

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of several heterocyclic amines formed during the cooking of proteinaceous foods. IQ is a potent carcinogen in rodent bioassays and causes a high incidence of hepatocellular carcinomas in nonhuman primates. We examined 20 hepatocellular carcinomas (HCCs) from nonhuman primates for mutations of the p53 gene using polymerase chain reaction-single strand conformational polymorphism analysis. Mutations in the p53 gene were detected in 4 of 20 HCCs (20%) with 3 showing G-to-T transversions and one a G-to-A transition. Three of these mutations were observed in codons 175 and 248 that are known mutational hot spots in human cancers. These data indicate that part of the IQ-induced HCCs in nonhuman primates may involve inactivation of the p53 gene and suggest that IQ and possibly other heterocyclic amines may participate in human carcinogenesis by a similar mechanism.

Animals↗
PubMed1994

Absence of p53 mutations in rat colon tumors induced by 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole, 2-amino-3-methylimidazo[4,5-f]quinoline, or 2-amino-1-methyl-6-phenylimidazo]4,5-b]pyridine.

Colon tumors were induced in F344 rats by three heterocyclic amines (HCAs), 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and examined for p53 mutations. Seven carcinomas induced by Glu-P-1, and nine carcinomas and two adenomas induced by IQ were examined by cDNA-polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis from codon 103 to 391 of p53, which encompasses the conserved regions II to IV. Nine carcinomas induced by PhIP were examined by genomic PCR-SSCP analysis of exons 5 to 7 (from codon 124 to 304), which encompasses the 3' half of the conserved region II and all the conserved regions III-V. No band shifts were found in any of these tumors under at least two conditions of SSCP analysis. Our previous study had shown a Ki-ras mutation in only one Glu-P-1-induced adenocarcinoma among the same 27 colon tumors, and no other mutation of ras family genes had been found. HCA-induced rat colon tumors appear to represent a group of human colon tumors in which neither Ki-ras nor p53 is involved.

Adenocarcinoma↗
PubMed1994

Suppression of G1 arrest and enhancement of G2 arrest by inhibitors of poly(ADP-ribose) polymerase: possible involvement of poly(ADP-ribosyl)ation in cell cycle arrest following gamma-irradiation.

Low-dose gamma-irradiation of mouse embryonic fibroblast C3D2F1 3T3-a cells caused G1 arrest along with G2 arrest and inhibition of replicative DNA synthesis. When the cells were cultured in the presence of inhibitors of poly(ADP-ribose) polymerase [EC 2.4.2.30], such as 3-aminobenzamide, benzamide and luminol, G1 arrest of C3D2F1 3T3-a cells was suppressed and enhancement of G2 arrest was observed. In contrast, 3-aminobenzoic acid, a non-inhibitory analog of 3-aminobenzamide, did not suppress G1 arrest following gamma-irradiation. These results suggest that the poly(ADP-ribosyl)ation reaction is critical for the pathway of G1 arrest and is also involved in the pathway of G2 arrest.

Animals↗
PubMed1994

Linkage analysis of BRCA1 in Japanese breast cancer families.

We examined the involvement of BRCA1, which plays a major role in Western breast cancer families, in Japanese breast cancer families. Eleven families, in which at least three individuals within third degree relatives were affected by breast cancer, were collected. Five of them were early-onset breast cancer families, in which the average age at diagnosis was less than 45 years, and the other six were late-onset families. Ovarian cancer was observed in one patient in the early-onset families. Using seven polymorphic markers on chromosome 17q21, D17S250, ERBB2, THRA1, D17S579, D17S588, GIP and NME1, linkage to BRCA1 was analyzed. Linkage was not detected in any single family. Assuming homogeneity in an inherited component that confines the susceptibility to breast cancer in all families, we summed the LOD scores of all families. The cumulative LOD score obtained was -1.86 for D17S588 at theta = 0.001, indicating no linkage with BRCA1. Since the proportion of families linked to BRCA1 is larger in Western early-onset breast cancer families than in late-onset ones, we also summed the LOD scores of five early-onset families. However, again a negative LOD score was obtained. These results suggest that BRCA1 is not a major breast cancer susceptibility gene in Japanese familial breast cancer.

Adult↗
PubMed1994

p53 gene mutations in human prostate cancers in Japan: different mutation spectra between Japan and western countries.

The involvement of p53 mutations in prostate cancers in Japan was investigated. To evaluate any possible clinicopathological significance, p53 mutations in 40 samples from 36 Japanese prostate cancers of different stages (five cases of latent tumors, three of stage A cancers, 10 of stage B, five of stage C and 13 of stage D), including four lymph node metastases of stage D cases, were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and sequencing. Mutations were detected in five of 40 samples (12.5%); four were in primary cancers and the other in a lymph node metastasis from one of them. All mutation-positive cases were in stage D, and the mutation frequency in stage D cases was 31%. This result indicates that p53 mutations may play a role in the progression of a subgroup of prostate cancers in Japanese, as observed for Americans and Europeans. However, a difference was noted between Japanese and Americans in the p53 mutational spectrum (at CpG site), presumably arising from variation in the underlying etiologic factors.

Aged↗
PubMed1994

Risks of antipyretics in young children with fever due to infectious disease.

The objective of this study was to determine whether paracetamol (acetaminophen) affects the outcome of children with fever due to bacterial infectious disease. A total of 208 outpatients aged 6 months to 15 years with pyrexia due to bacterial infection who had been examined at the Fujimoto Children's Hospital from March 1992 to May 1992. The number of antipyretic doses of paracetamol (10 mg/kg) a day received within 3 days of illness in the patients with acute fever (> or = 38 degrees C) was investigated. In this study, the patients were divided into two groups: (i) the pneumonia group, which consisted of 101 patients who were subsequently diagnosed as having pneumonia during their illness and (ii) the control group, which consisted of 107 patients who were subsequently diagnosed as having illness with fever that did not progress to pneumonia. The mean number of daily doses was significantly higher for the pneumonia group (2.52 +/- 0.80) than for the control group (1.37 +/- 0.72, P < 0.001). There was no significant difference between the pneumonia group and the control group in body temperature during acute fever (38.7 +/- 0.65 vs 38.8 +/- 0.54 degrees C). The data suggest that frequent administration of antipyretics to children with infectious disease may lead to a worsening of their illness.

Acetaminophen↗
PubMed1994

Intravascular ultrasound of coronary arteries in children. Assessment of the wall morphology and the lumen after Kawasaki disease.

BACKGROUND: The long-term clinical issue in Kawasaki disease (KD) concerns the coronary artery lesion. Two-dimensional echocardiography and coronary angiography are routine examinations to evaluate the coronary lesions; however, these are not adequate to assess the wall morphology of the coronary artery (CA). Intravascular ultrasound imaging (IVUS), a new technology for the evaluation of the coronary artery lumen and wall morphology in vivo, was performed for patients after KD in their long-term follow-up, and we examined the new insights it gave. METHODS AND RESULTS: IVUS was performed during cardiac catheterization in 20 subjects (10 patients after KD who still had coronary aneurysms or regressed coronary aneurysms, 2 after KD who had no coronary abnormal lesion, and 8 control patients with congenital heart disease and normal CA). We evaluated the wall structure at 10 to 15 sites of the CA in each patient. IVUS was performed with a commercially available ultrasound imaging catheter. Four sites of a CA aneurysm in KD demonstrated a markedly dilated lumen without thickened intima. One site of a CA aneurysm with calcification demonstrated an asymmetrical lumen by a dense echo with acoustic shadows. Twenty-two sites of a regressed CA aneurysm demonstrated a marked symmetrical or asymmetrical thickening of the intima with a dense echo, in which the size of the lumen was similar to that at a site near a regressed aneurysm. The sites of angiographically normal CA revealed normal structures and a thin intima in many instances. Nine of 28 sites in KD with a CA abnormal lesion, particularly near a coronary aneurysm or regressed aneurysm, demonstrated a mild thickening of the intima. All the 10 sites in KD without a CA abnormal lesion and all the 25 sites in patients with congenital heart disease with normal CA demonstrated a smooth intima. CONCLUSIONS: This study demonstrated that the site of a regressed coronary aneurysm has a markedly thickened but smooth intima. The sites of angiographically normal CA after KD with or without a coronary lesion demonstrated normal IVUS findings in most instances but in some cases revealed a mild intimal thickening. IVUS is useful to evaluate the CA wall morphology and may contribute to the assessment of long-term CA sequelae and the possible development of arteriosclerotic changes in KD.

Adolescent↗
PubMed1994

Induction of hepatocellular carcinoma in nonhuman primates by the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline.

The heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was evaluated for carcinogenic effects in macaques, primarily cynomolgus monkeys. IQ was administered by gavage five times a week at doses of 10 or 20 mg/kg. IQ induced hepatocellular carcinoma in 55% of the animals at the low dose and in 95% of the animals at 20 mg/kg. The average latent period at the high dose level was 43 months and that at the low dose was 60 months. Generally, the tumor nodules exhibited a well- to moderately well-differentiated hepatocellular carcinoma, and a trabecular pattern was most frequently seen. Pulmonary metastases were also found in several of the monkeys. Thus, IQ is a potent carcinogen in nonhuman primates and is a potential carcinogen for humans.

Animals↗
PubMed1994

The role of fat and calcium in the production of foci of aberrant crypts in the colon of rats fed 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine.

The modulation by dietary fat levels of intestine carcinogenesis is well documented. New developments suggest that calcium ions may also play a role. A rapid bioassay, the induction of foci of aberrant crypts in the colon, was used to explore the interaction between dietary fat and calcium. Male F344 rats 6 weeks of age were placed on diets containing 5 or 20% corn oil, and 0.04 or 0.32% calcium ion, as calcium lactate. Each dietary group was fed 400 ppm 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), and negative controls received the diets alone. A positive control group was given 2 mg N-nitrosomethylurea (NMU) intrarectally four times in a 2-week period. All rats were killed after 9 weeks. The intestinal tract was rinsed with Krebs-Ringer buffer. After staining a 6-cm segment of the descending colon and rectum with 0.2% methylene blue, foci of aberrant crypts were evaluated microscopically. With PhlP as a carcinogen, the rats on a high-fat, low-calcium level had more foci of aberrant crypts than animals on a low-fat level. With the higher calcium level, there were fewer foci and aberrant crypts, but the effect of fat was still significant. With NMU and a low-calcium level, the effect of fat level was evident. However, with the higher calcium intake, there were considerably more foci of aberrant crypts than on the low-calcium level, and the effect of the dietary fat level was not obvious.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Isolation and serological characterization of porcine reproductive and respiratory syndrome (PRRS) viruses from pigs with reproductive and respiratory disorders in Japan.

Three porcine reproductive and respiratory syndrome viruses (PRRSVs) were successfully isolated from stillborn piglets and fattening pigs derived from different herds affected either with an epizootic reproductive failure or a severe chronic respiratory distress in Japan. The isolates were reacted with antisera against both European (Lelystad virus) and American (strain 46448) PRRSVs in indirect immunofluorescence (IIF). However, cross immunoperoxidase monolayer assay revealed the close serological relationships between the Japanese isolates and American PRRSV, but not between the Japanese isolates and the European PRRSV. The data of preliminary serological survey with IIF technique showed a high frequency of antibody positive pigs against both Japanese isolate and the American PRRSV, whereas a low frequency of antibody positive pigs against the European PRRSV, on herds which have had clinical episodes of PRRS-like diseases. These results indicate that PRRSVs are prevalent in Japan, and suggest that the antigenicities of the prevalent PRRSVs are more closely related to those of the American than the European PRRSVs.

Animals↗