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Biomedical subjects

T Sugimura

Publications and source records attributed to T Sugimura.

At least 109 records · Page 6Linked to original sources
PubMed1999

Difference in target organs in carcinogenesis with a heterocyclic amine, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, in different strains of mice.

2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) induces cancers in the forestomach and liver, but not in the colon, of CDF1 male and female mice, which are thought to be resistant to induction of colon cancer by 1,2-dimethylhydrazine. In this study, we examined the carcinogenicity of MeIQ in C57BL/6N female mice, which are susceptible to 1,2-dimethylhydrazine. This strain of mice developed carcinomas of the cecum, colon and liver, but not the forestomach, when given a diet containing 300 ppm of MeIQ. This fact indicates that the target organs of a chemical carcinogen change depending on the strain of a given animal species.

1,2-Dimethylhydrazine↗
PubMed1999

Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats.

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti-carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2-week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6-week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN-76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.

Aminobiphenyl Compounds↗
PubMed1999

Lack of carcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in cynomolgus monkeys.

The carcinogenic potential of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was evaluated in cynomolgus monkeys. The animals received MeIQx, beginning at the age of one year, at doses of 10 or 20 mg/kg body weight by gavage five times a week for 84 months and were autopsied 8 months thereafter. Although sporadic development of aberrant crypt foci in the colon and glutathione S-transferase pi-positive foci in the liver as well as hyperplastic changes of the lymphatic tissue in the lung and gastro-intestinal tract were observed in several monkeys, this was not treatment-related. No neoplastic or preneoplastic lesions were found in other organs. Serum chemistry data and organ weights were also within the normal ranges. From these data, it is concluded that MeIQx is not carcinogenic in the cynomolgus monkey under the conditions examined. This lack of carcinogenicity is probably related to the poor activation of MeIQx due to the lack of constitutive expression of CYP1A2 as well as an inability of other cytochrome P450s to catalyze N-hydroxylation of MeIQx in the cynomolgus monkey.

Animals↗
PubMed1999

Sweet taste responses of mouse chorda tympani neurons: existence of gurmarin-sensitive and -insensitive receptor components.

Inhibitory effects of gurmarin (gur) on responses to sucrose and other sweeteners of single fibers of the chorda tympani nerve in C57BL mice were examined. Of 30 single fibers that strongly responded to 0. 5 M sucrose but were not or to lesser extent responsive to 0.1 M NaCl, 0.01 M HCl, and 0.02 M quinine HCl (sucrose-best fibers), 16 fibers showed large suppression of responses to sucrose and other sweeteners by lingual treatment with 4.8 microM (approximately 20 microg/ml) gur (suppressed to 4-52% of control: gur-sensitive fibers), whereas the remaining 14 fibers showed no such gur inhibition (77-106% of control: gur-insensitive fibers). In gur-sensitive fibers, responses to sucrose inhibited by gur recovered to approximately 70% of control responses after rinsing the tongue with 15 mM beta-cyclodextrin and were almost abolished by further treatment with 2% pronase. In gur-insensitive fibers, sucrose responses were not inhibited by gur, but were largely suppressed by pronase. These results suggest existence of two different receptor components for sweeteners with different susceptibilities to gur in mouse taste cells, one gur sensitive and the other gur insensitive. Taste cells possessing each component may be specifically innervated by a particular type of chorda tympani neurons.

Animals↗
PubMed1999

Quantification of two aromatic amine mutagens, PBTA-1 and PBTA-2, in the yodo river system.

The levels of two aromatic amine mutagens, 2-[2-(acetylamino)-4-[bis(2-methoxyethyl)amino]-5-methoxyphenyl]-5-am ino-7-bromo-4-chloro-2H-benzotriazole (PBTA-1) and 2-[2-(acetylamino-4-[N-(2-cyanoethyl)ethylamino]-5-methoxyphenyl]-5-a mino-7-bromo-4-chloro-2H-benzotriazole (PBTA-2), were quantitatively analyzed in the Yodo River system in Japan. The river water samples were collected at nine sampling sites from the Yodo River system twice or three times between May and July in 1997. PBTA-1 and PBTA-2 in the river water samples were concentrated on blue rayon columns, partially purified by high-performance liquid chromatography (HPLC) on reverse-phase columns, then quantified by HPLC with an electrochemical detector. The amounts of PBTA-1 and PBTA-2 in the water samples were < 0.01-1.91 and < 0.01-2.25 ng/L, respectively. High levels of PBTA-1 and PBTA-2 were detected in the samples collected within 4 km downstream of two sewage plants, which are located along the banks of the Nishitakase River, a tributary of the Yodo River system, and these samples showed stronger mutagenicity in Salmonella typhimurium YG1024 with S9 mix than the other water samples. On the other hand, the river water samples from upstream of the sewage plant were weakly or not mutagenic and PBTA-1 and PBTA-2 were not detected. These results confirmed that a major source of PBTA-1 and PBTA-2 in the Yodo River system is effluent from the sewage plants and that discharged mutagens, including PBTA-1 and PBTA-2, are diluted and/or decomposed while moving down the Yodo River system.

Chromatography, High Pressure Liquid↗
PubMed1999

Analysis of the N-terminal polypeptide of the capsid precursor protein and the ORF3 product of feline calicivirus.

The N-terminal unique polypeptide region of the capsid precursor protein of feline calicivirus (FCV) and the protein encoded by ORF3 of FCV were expressed as fusion proteins with glutathione S-transferase to analyze the expressed products in FCV-infected cells. Immunoblot analysis using a serum from a cat experimentally infected with FCV indicated relatively high immunogenicity of the N-terminal polypeptide in FCV-infected cats, as compared with the ORF3 protein. Specific antisera were prepared by immunization to mice with the fused proteins and used in immunoblot analysis. A 14 kD product corresponding to the N-terminal polypeptide and a 10 kD polypeptide of the ORF3 product were identified in the FCV-infected cells but not detected in the purified particles. No neutralization activity against FCV was detected in these antisera. The proteins identified as polypeptides of 14 kD and 10 kD in this study may have functions as non-structural proteins.

Animals↗
PubMed1999

[Psychogenic lower urinary tract dysfunction in women: patho-physiological investigation for psychogenic frequency-urgency syndrome and psychogenic urinary retention].

PURPOSE: Psychogenic lower urinary tract dysfunction (PLUTD) is composed of two syndromes; psychogenic frequency-urgency syndrome (PFUS) and psychogenic urinary retention (PUR). We evaluated the patho-physiology of PFUS and PUR, and explored the different pathogenesis in these syndromes. MATERIAL AND METHODS: Forty five patients with PLUTD, consisting of 23 patients with PFUS and 22 patients with PUR were investigated by using the psychological tests: CMI (Cornell Medical Index) and TEG (Todai's Egogram), a quantitative perspiration test in 45 females (23 patients with PFUS and 22 patients with PUR), and simultaneous measurements of voiding cysto-urethrography and urodynamic studies using the Life-Tech 6 channel polygraph in 35 patients (17 patients with PFUS and 18 patients with PUR). RESULTS: The prevalence in ages revealed two peaks, 20 years and 50 to 60 years. Over 25% of them had pyuria more than 10/hpf of WBC. Peak flow rate measured by uroflowmetry showed normal range in PFUS group and decreased in PUR group. The functional vesical volume was less than 100 ml in most patients with PFUS. Residual urine in PUR group was significantly greater. Capacity of the PFUS group were able to hold over 400 ml of contrast instilled through the urethral catheter, despite increased desire to void. Over 15% of the study group with PFUS showed uninhibited systolic contraction of detrusor (> 15 cm H2O) during filling phase. The measurement value of urodynamic parameters demonstrated that a periodic follow-up survey of the upper urinary tract should be performed because of the low compliance bladder in the patients with PLUTD. During voiding phase, the women with PFUS had a tendency to be divided into two groups, hypercontractile or acontractile detrusor. The voiding cysto-urethrography (VCUG) showed a tendency of bladder neck opening on patients with PFUS during filling phase. Most of PLUTD cases demonstrated a round to triangle shape on vesical configuration, which led to a spastic condition of detrusor muscle. We attempted to measure the quantitative perspiration using 3 kinds of loading tests; respiratory, arithmetic and psychological load. In the psychological loading test, we asked 98 questions about their daily lives including occupation, living condition, family relationship and sexual activities. Arithmetic loading test consisted of counting in reverse, subtraction and multiplication. The quantitative perspiration rate resulted in a "positive" in many patients with PFUS. Respiration loading test was performed to measure the respiration volume during 3 large inhales. Most patients with PUR tested within the normal range for respiration except for those patients with decreased or no perspiration during the psychiatric loading test. These results may reflect the psychological elements including suppression and subconscious defense mechanism. Neurosis which was diagnosed as having type III to type IV of the Cornell Medical Index was demonstrated in less than under 40% of patients with PFUS and more than 55% patients with PUR. There was no significant trend or difference between PFUS and PUR detected from Todai's Egogram. CONCLUSIONS: Due to the reflection of many psychological responses, it is necessary to investigate from various examinations including psychological, autonomical and classical urological studies for accurate diagnosis of PLUTD.

Adolescent↗
PubMed1999

Function of poly(ADP-ribose) polymerase in response to DNA damage: gene-disruption study in mice.

To elucidate the biological functions of poly(ADP-ribose) polymerase (PARP, [EC 2.4.2.30]) in DNA damage responses, genetic and biochemical approaches were undertaken. By disrupting exon 1 of the mouse PARP gene by a homologous recombination, PARP-deficient mouse embryonic stem (ES) cell lines and mice could be produced without demonstrating lethality. PARP-/- ES cells showed complete loss of PARP activity and increased sensitivity to gamma-irradiation and an alkylating agents, indicating a physiological role for PARP in the response to DNA damage. p53, a key molecule in cellular DNA damage response, was found to stimulate PARP activity and became poly(ADP-ribosyl)ated in the presence of damaged DNA. However, PARP-/- ES cells showed p21 and Mdm-2 mRNA induction following gamma-irradiation, indicating that PARP activity is not indispensable for p21 and Mdm-2 mRNA induction in the established p53-cascade. On the other hand, in a reconstituted reaction system, purified PARP from human placenta suppressed the pRB-phosphorylation activity in the presence of NAD and damaged DNA. Human PARP expressed in E. coli showed a similar effect on pRB-phosphorylation activity of cdk2. These findings suggest a direct involvement of PARP in the regulation of cdk activity for cell-cycle arrest.

Animals↗
PubMed1998

Consecutive in vivo measurement of nitric oxide in transient forebrain ischemic rat under normothermia and hypothermia.

The effects of hypothermia on production of nitric oxide (NO) in ischemic brain were investigated by using in vivo microdialysis. Male Wistar rats were randomly divided into three groups; saline-treated normothermic group (37 degreesC, n=6), 30 mg/kg N-nitro-l-arginine methyl ester(l-NAME)-treated normothermic group (n=6), and saline-treated hypothermic group (30 degreesC, n=6). Transient forebrain ischemia was produced by bilateral common carotid artery occlusion combined with hypotension (MABP=50 mmHg). Saline-treated normothermic animals resulted in a reduction of LCBF to 9% of baseline. Saline-treated hypothermic rats revealed the similar changes of LCBF. In contrast, l-NAME administration reduced the basal CBF to 85% of saline-treated group and to 8% after ischemia. NO products were decreased during ischemia and transiently increased after reperfusion in saline-treated groups. However, the increase of NO products after reperfusion was less significant in the hypothermia. l-NAME-treated group showed a constant reduction of NO production during ischemia and after reperfusion.

Animals↗
PubMed1998

Cancer prevention: past, present, future.

There are many examples of different types of cancers that have been prevented by appropriate measures in the past. Most of them were related to occupational, iatrogenic or accidental factors, often as the outcome of heavy exposure of humans to specific carcinogenic agents. Cancer is a disease of DNA, and is generally associated with multiple genetic alterations, these being produced in the typical case by exposure to various carcinogens, each of which exists at minute concentrations. Thus, the impact of carcinogenic factors, xenobiotics and autobiotics, is due to their actions in concert. However, a single mutation yielding genomic instability exerts a disproportionately large influence by resulting in a large number of secondary mutational events. Epigenetic changes can also not be disregarded especially from the view point of prevention of neoplasia. The occurrence of multiple primary cancers among survivors of initial primaries, and the presence of hereditary groups with a high risk of cancer development provide a strong stimulus for establishment of effective approach for cancer prevention, which should be, in principle, multi-faceted. Therefore, a holistic approach is essential with improvement in life style including choosing a balanced diet and avoidance of cigarette smoking and other sources of carcinogens, as integral elements.

Anticarcinogenic Agents↗
PubMed1998

Genetic determinant and environmental carcinogens.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant mutagenic heterocyclic amine (HCA) present in cooked foods. PhIP induces colon cancer in male Fischer 344 (F344) rats, and its role in human colon carcinogenesis has been suspected. To study the ecogenetics in PhIP colon carcinogenesis, rat system using aberrant crypt focus (ACF) formation as a phenotypic marker was applied. Among Buffalo (BUF), Brown Norway (BN), F344 and ACI/N (ACI) strains of rats, F344 rats produced a lower level of PhIP-DNA adducts than other three strains, and the number of ACFs/rat was highest in BUF, intermediate in BN and F344 and lowest in ACI. Thus there was no correlation between adduct levels and number of ACF induced by PhIP. F1 progenies of BUF and ACI developed ACF at a similar level to that of F344, and F1 progenies of F344 and ACI developed ACF at a similar level to that of F344. Thus it was indicated that susceptibility of F344 to the ACF induction was autosomally dominant over ACI rats. The results also suggest that BUF rats have at least two genes, one is autosomally recessive against ACI rats and one is autosomally dominant similar to that F344 has. A total of 170 progeny of ACI backcross of F344/ACI F1 were examined for number of ACFs and 65 progeny were phenotyped as F344 and 60 were ACI. Using these 125 rats, chromosomal mapping is being performed using markers of simple sequence length polymorphism (SSLP) and representational difference analysis (RDA). By mapping the gene, we will be able to identify humans who might belong to high risk group in general population, and cancer can be prevented more efficiently by attaining early diagnosis.

Animals↗
PubMed1998

Inhibitory effects of antioxidants on formation of heterocyclic amines.

It is important to search for effective antioxidants to suppress formation of mutagenic and carcinogenic heterocyclic amines (HCAs), like 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), because these HCAs are considered to be probable human carcinogens. The effects of various food-derived antioxidants on MeIQx formation were examined by their addition (0.2 mmol each) to mixtures of creatine (0.4 mmol), glycine (0.4 mmol) and glucose (0.2 mmol), and heating at 128 degreesC for 2 h. Glycine was replaced by l-phenylalanine in the case of PhIP formation. Among the 14 kinds of antioxidants tested, green tea catechins and the major component [(-)-epigallocatechin gallate], two flavonoids (luteolin and quercetin) and caffeic acid were found to clearly suppress the formation of both MeIQx and PhIP, being 3.2-75% of the level of the controls. These phenolic antioxidants also reduced the total mutagenicity of the heated mixtures. The results suggest that foodstuffs containing catechins, flavonoids and caffeic acid may suppress the formation of HCAs in cooked foods.

Animals↗
PubMed1998

No direct correlation between mutant frequencies and cancer incidence induced by MeIQ in various organs of Big Blue mice.

The carcinogenicity of 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) was examined in Big Blue female mice with the genetic background of C57BL/6N. With the administration of 300 ppm of MeIQ in their diet for 92 weeks, the Big Blue female mice developed intestinal tumors and hepatocellular carcinomas. The incidences of adenocarcinomas were 42% (8/19) in the colon and 68% (13/19) in the cecum. The incidence of hepatocellular carcinomas was 84% (16/19). No carcinomas of the intestine or the liver were induced in the control group. As we previously reported, administration of 300 ppm of MeIQ in a diet for 12 weeks induced lacI mutants at the highest frequency in colonocytes, and at only less than one-tenth of the colon in cells of the liver, forestomach and bone marrow, indicating no direct correlation between the lacI mutant frequency (MF) and cancer incidence (CI). The fate of cells with lacI mutation in each organ should be taken into consideration to validate MF as an indicator of carcinogenic potency of a chemical in different organs.

Animals↗
PubMed1998

High frequency of beta-catenin (ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat.

Activating mutations in the beta-catenin (CTNNB1) gene corresponding to N-terminal phosphorylation sites in the protein have been implicated in the development of human colon cancer. To determine the possible involvement of such mutations during chemically induced colon carcinogenesis, we examined the corresponding region of Ctnnb1 in colon tumors induced in the F344 rat by two cooked meat heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). All of the colon tumors induced by 2-amino-3-methylimidazo[4,5-f]quinoline that were examined (5 of 5) and 4 of 7 PhIP-induced colon tumors had mutations within or flanking codons corresponding to important phosphorylation sites in beta-catenin. None of the colon tumors bearing Ctnnb1 mutations had genetic changes in the Apc gene, and those that contained wild-type Ctnnb1 were known from our previous work to contain Apc mutations. The results provide evidence for a major role of the beta-catenin/Apc pathway in the development of heterocyclic amine-induced colon tumors and give further weight to the view that regulation of beta-catenin is critical to the tumor suppressive effects of Apc during colon carcinogenesis. In contrast, Ctnnb1 mutations were completely absent in 23 PhIP-induced mammary tumors, in accordance with recent work showing that human breast carcinomas lack mutations in CTNNB1.

Animals↗