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Biomedical subjects

T Sugimura

Publications and source records attributed to T Sugimura.

At least 523 records · Page 29Linked to original sources
PubMed1988

Oxidation of the 2-hydroxyamino derivative of 2-amino-6-methyl-dipyrido[1,2-a: 3',2'-d] imidazole (Glu-P-1) to its 2-nitroso form, an ultimate form reacting with hemoglobin thiol groups.

The binding to hemoglobin of synthetic 2-hydroxyamino-6-methyldipyrido[1,2-a: 3',2'-d] imidazole from the carcinogenic product of L-glutamic acid pyrolysis 2-amino-6-methyldipyrido[1,2-a: 3',2'-d] imidazole were investigated in vitro. The hydroxylamine required oxidation to its nitroso derivative to bind to rat hemoglobin through thiol groups. Oxidation of the hydroxylamine to the nitroso form was found to be enhanced by oxyhemoglobin and superoxide dismutase at pH 7.4 under aerobic conditions. Since these conditions might also enhance this oxidation in vivo, the conversion of the DNA-reactive arylhydroxylamines to the DNA-non-reactive nitroso compounds and their subsequent binding to highly abundant thiol groups of proteins could be considered as a process for detoxification of toxic arylhydroxylamines.

Animals↗
PubMed1988

Non-enzymatic glutathione conjugation of 2-nitroso-6-methyldipyrido [1,2-a: 3',2'-d] imidazole (NO-Glu-P-1) in vitro: N-hydroxy-sulfonamide, a new binding form of arylnitroso compounds and thiols.

In order to study the possible detoxification mechanisms of the carcinogenic arylamine, 2-amino-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (Glu-P-1), the in vitro non-enzymatic reaction of 2-nitroso-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (NO-Glu-P-1) with reduced glutathione (GSH) was examined at pH 7.4 under both aerobic and anaerobic conditions. Two GSH-arylamine adducts were isolated and found to contain the Glu-P-1 and GSH moieties in a 1:1 molar ratio via an N-S linkage. Their structures were assigned as sulfinamide (-NH-SO-) and N-hydroxy-sulfonamide (-N(OH)-SO2-) by their behaviour under acidic and basic conditions and by UV-VIS, 1H-NMR, infrared and mass spectrometries. Also, a N-hydroxy-sulfonamide adduct was produced when NO-Glu-P-1 and cysteine were reacted at pH 7.4. The N-hydroxy-sulfonamide structure is a new binding form between arylnitroso compounds and thiols. The formation of these adducts may also take place in vivo as a detoxification of toxic arylamines since GSH is abundant in organs such as liver or kidney.

Chromatography, High Pressure Liquid↗
PubMed1988

Mutagenic and carcinogenic heterocyclic amines in Chinese cooked foods.

Samples of 7 foods commonly eaten in the Northeast of China (i.e. fried and broiled fishes and broiled meat) were tested for mutagenicity on Salmonella typhimurium TA98 with S9 mix. The basic fractions of the samples were mutagenic, inducing 33-2930 revertants/g of cooked food. Fried walleye pollack (a kind of cod fish heated on a stainless steel pan) showed the highest mutagenicity, so attempts were made to isolate mutagens from the basic fraction of this food. The mutagens were purified by treatment with blue cotton and HPLC on a semi-preparative ODS column and analytical cation exchange and ODS columns. 5 mutagens were isolated and identified as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). 1 g of fried fish was estimated to contain 0.16 ng of IQ, 0.03 ng of MeIQ, 6.44 ng of MeIQx, 0.10 ng of 4,8-DiMeIQx and 69.2 ng of PhIP. MeIQx and PhIP accounted for 24% and 4.7%, respectively, of the total mutagenicity. The other 3 heterocyclic amines were each responsible for only 0.3-1.2% of the total mutagenicity.

China↗
PubMed1988

Presence of nitrosable mutagen precursors in cooked meat and fish.

Broiled chicken, pork, mutton, beef and sun-dried sardine were found to yield direct-acting mutagenicity after nitrite treatment. When 50% methanol extracts of cooked foods were treated with 50 mM nitrite at pH 3 for 1 h at 37 degrees C, they induced 3800-17,900 revertants of Salmonella typhimurium TA100 and 15,000-43,600 revertants of TA98 per g. In contrast, raw meat and uncooked sun-dried sardine showed little or no mutagenicity after nitrite treatment. Treatment of broiled chicken with 0.5-3 mM nitrite, which is a physiologically feasible concentration in the human stomach under some conditions, induced direct-acting mutagenicity. When broiled chicken was treated with 1 mM nitrite at pH 3 for 1 h at 37 degrees C, its mutagenicities on TA100 and TA98 without S9 mix were 7100 and 5400 revertants/g, respectively.

Animals↗
PubMed1988

The inhibitory effect of thioproline on carcinogenesis induced by N-benzylmethylamine and nitrite.

Thioproline, which is readily nitrosated to form nitrosothioproline, is expected to act as a nitrite scavenger. The effect of thioproline as an inhibitor of the carcinogenesis induced by N-nitroso-N-benzylmethylamine precursors was examined. Two groups of male F-344 rats were given diet containing 0.25% N-benzylmethylamine (group I) or 0.25% N-benzylmethylamine plus thioproline (0.25% until wk 17 and then 0.5%; group II). Both groups were given drinking-water containing sodium nitrite (0.1% until wk 17 and then 0.2%). The experiment was continued for 717 days. Squamous cell carcinoma of the forestomach developed in six out of seven rats in group I and in significantly fewer, two out of nine rats, in group II. The degree of invasion by the tumours was also less in group II rats, given thioproline, than in group I. Thus thioproline suppressed carcinogenesis induced by N-benzylmethylamine and nitrite, possibly by inhibiting the in vivo nitrosation of N-benzylmethylamine.

Animals↗
PubMed1988

DNA adducts formed by the comutagens harman and norharman in various tissues of mice.

Covalent modifications of DNA in various tissues of mice with harman or norharman were analyzed by 32P-postlabeling assay. Administration of 0.1% harman to mice in their diet for 4 weeks resulted in DNA adducts in the liver and kidney. No specific DNA adduct was detected in other tissues, such as the glandular stomach, large intestine and brain. Similar treatment of mice with norharman resulted in DNA adducts in the kidney, glandular stomach and large intestine, but not in the liver or brain. These results suggests the in vivo genotoxicities of harman and norharman.

Alkaloids↗
PubMed1988

Human HST1 (HSTF1) gene maps to chromosome band 11q13 and coamplifies with the INT2 gene in human cancer.

The human HST1 gene, previously designated the hst gene, and now assigned the name HSTF1 for heparin-binding secretory transforming factor in human gene nomenclature, was originally identified as a transforming gene in DNAs from human stomach cancers by transfection assay with mouse NIH 3T3 cells. The amino acid sequence of the product deduced from DNA sequences of the HST1 cDNA and genomic clones had approximately 40% homology to human basic and acidic fibroblast growth factors and mouse Int-2-encoded protein. We have mapped the human HST1 gene to chromosome 11 at band q13.3 by Southern blot hybridization analysis of a panel of human and mouse somatic cell hybrids and in situ hybridization with an HST1 cDNA probe. The HST1 gene was found to be amplified in DNAs obtained from a stomach cancer and a vulvar carcinoma cell line, A431. In all of these samples of DNA, the INT2 gene, previously mapped to human chromosome 11q13, was also amplified to the same degree as the HST1 gene.

Animals↗
PubMed1988

Deletion of transfected oncogenes from NIH 3T3 transformants by inhibitors of poly(ADP-ribose) polymerase.

a1-1 cells, a transformant line obtained by transfection of NIH 3T3 cells with human c-Ha-rasT24 (hc-Ha-rasT24), were converted to morphologically normal flat cells following a 2-week culture in the presence of benzamide (BA), an inhibitor of poly(ADP-ribose) polymerase [ADP-ribosyltransferase (polymerizing); EC 2.4.2.30]. Concomitant with these morphological changes was the loss of the exogenous hc-Ha-rasT24 sequence. When cells were cultured without transfer, multiple clusters of flat revertant cells surrounded by transformed cells within single colonies of a1-1 cells were observed. This, together with the slow growth rate of flat cells in the presence of BA, indicated that flat revertants were induced rather than selected by BA. Flat cells isolated from mixed colonies completely lost the exogenous and amplified hc-Ha-rasT24 gene. In contrast, the endogenous mouse c-Ha-ras in flat revertant cells was not lost during culture with BA. Similarly, the endogenous hc-Ha-rasT24 in human bladder carcinoma T24 cells was not affected by BA. By using various chemicals, it was suggested that inhibition of poly(ADP-ribose) polymerase induces an efficient and specific loss of the exogenous transforming genes including Ki-ras, N-ras, c-raf, and ret-II.

Animals↗
PubMed1988

Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter.

Okadaic acid is a polyether compound of a C38 fatty acid, isolated from a black sponge, Halichondria okadai. Previous studies showed that okadaic acid is a skin irritant and induces ornithine decarboxylase (OrnDCase; 3-hydroxyl-L-glutamate 1-carboxy-lyase, EC 4.1.1.17) in mouse skin 4 hr after its application to the skin. This induction was strongly inhibited by pretreatment of the skin with 13-cis-retinoic acid. A two-stage carcinogenesis experiment in mouse skin initiated by a single application of 100 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA) and followed by application of 10 micrograms of okadaic acid twice a week revealed that okadaic acid is a potent additional tumor promoter: tumors developed in 93% of the mice treated with DMBA and okadaic acid by week 16. In contrast, tumors were found in only one mouse each in the groups treated with DMBA alone or okadaic acid alone. An average of 2.6 tumors per mouse was found in week 30 in the group treated with DMBA and okadaic acid. Unlike phorbol 12-tetradecanoate 13-acetate (TPA), teleocidin, and aplysiatoxin, okadaic acid did not inhibit the specific binding of [3H]TPA to a mouse skin particulate fraction when added up to 100 microM or activate calcium-activated, phospholipid-dependent protein kinase (protein kinase C) in vitro when added up to 1.2 microM. Therefore, the actions of okadaic acid and phorbol ester may be mediated in different ways. These results show that okadaic acid is a non-TPA-type tumor promoter in mouse skin carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Carcinogenicity in rats of a mutagenic compound, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline.

Carcinogenicity of 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx), which is a potent mutagen first isolated from fried beef and widely present in various cooked foods, was tested in both sexes of F344 rats. Rats were continuously given a diet containing 0.04% MeIQx or basal diet and the experiment was finished on day 429. In experimental animals, the incidence of liver, Zymbal gland, clitoral gland and skin tumors was significantly higher than in control animals. The incidence of liver tumors was 100% in males and 53% in females; most liver tumors of males were hepatocellular carcinomas and all liver tumors of females were neoplastic nodules. The incidence of Zymbal gland tumors was 75% in males and 53% in females. Clitoral gland tumors were induced in 63% and skin tumors were observed in 35% of males and 5% of females. Most of these three types of tumors were diagnosed as squamous cell carcinoma. In the control rats, liver, Zymbal gland, clitoral gland and skin tumors were not observed in either sex.

Animals↗
PubMed1988

Use of the 32P-postlabeling method to detect DNA adducts of 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ) in monkeys fed IQ: identification of the N-(deoxyguanosin-8-yl)-IQ adduct.

Eight DNA adducts of 2-amino-3-methylimidazolo[4,5-f]-quinoline (IQ) were found by the standard 32P-postlabeling method in livers from male Cynomolgus monkeys fed IQ (5 days/week, 3 weeks, 20 mg/kg, nasal-gastric intubation). The IQ-DNA adduct fingerprints observed in monkeys were identical to those observed in rats that received IQ (0.03%) in the diet for 2 weeks. The C8-guanine-IQ adduct was identified by comigration with the synthetic 3',5'-bisphosphate derivative of N(-deoxyguanosin-8-yl)-IQ. DNA modified in vitro with N-hydroxy-IQ showed seven adducts, including the C8-guanine-IQ adduct, that were identical to those found in monkeys and rats. Thus it appears that N-hydroxy-IQ, the reactive metabolite of IQ, was responsible for all adducts found in vivo, except one. In order to detect adducts in other organs that were present at lower levels, the intensification (ATP-deficient) method for 32P-postlabeling was used. Five of the adducts detected under standard conditions, including the C8-guanine-IQ adduct, were also detected under intensification conditions. The total level of DNA-IQ adducts was highest in the liver, followed by the kidney, colon and stomach, and bladder. The adduct patterns were identical in all organs examined. The results indicate that IQ is potentially genotoxic in primates and therefore a likely human carcinogen.

Animals↗
PubMed1988

32P-postlabeling analysis of DNA adducts in rat stomach with 1-nitrosoindole-3-acetonitrile, a direct-acting mutagenic indole compound formed by nitrosation.

Modification of DNA by a direct-acting mutagen, 1-nitrosoindole-3-acetonitrile, which is formed from indole-3-acetonitrile upon nitrite treatment, was investigated. 32P-Postlabeling analysis clearly demonstrated the formation of DNA adducts in the stomach of rats after intragastric administration of 1-nitrosoindole-3-acetonitrile. The level of DNA adducts in both the forestomach and glandular stomach 2 h after administration of 100 mg/kg body weight of the compound was about one adduct per 10(7) nucleotides. The DNAs of the forestomach and glandular stomach gave six common spots on two-dimensional chromatography, three of which were also produced by in vitro reaction of this compound with DNA. Thus, 1-nitrosoindole-3-acetonitrile can form DNA adducts in vivo and in vitro. No DNA adducts were detected after treatment with the non-nitrosated compound indole-3-acetonitrile both in vivo and in vitro. These results suggest that 1-nitrosoindole-3-acetonitrile has the in vivo tumor initiating activity in the stomach.

Acetonitriles↗
PubMed1988

In vitro reaction of hydroxyamino derivatives of MeIQx, Glu-P-1 and Trp-P-1 with DNA: 32P-postlabelling analysis of DNA adducts formed in vivo by the parent amines and in vitro by their hydroxyamino derivatives.

The synthetic hydroxyamino derivatives of three mutagenic and carcinogenic heterocyclic amines present in cooked foods and amino acid pyrolysates, 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), were reacted with DNA in vitro. Their reactivities were increased by addition of 10-fold excess of acetic anhydride. 32P-Postlabelling analysis of the adducts formed in these in vitro reactions revealed that almost all the adducts of the hydroxyamino derivatives of MeIQx and Glu-P-1 were the same as those formed in liver DNA of rats intragastrically treated with the parent amines. In contrast, analysis of Trp-P-1--DNA adducts showed that the adducts formed in vitro were minor components of those formed in vivo; the two main adducts formed in vivo were not formed in vitro. Thus, MeIQx and Glu-P-1 may be metabolized in vivo to hydroxyamino derivatives and/or their esterified forms, such as N-acetoxy derivatives that form DNA adducts. Formation of adducts by Trp-P-1, however, may occur through more complicated metabolic pathways. Elucidation of the structures of DNA adducts in vivo is necessary to clarify this problem.

Animals↗
PubMed1988

Amplification of the hst-1 gene in human esophageal carcinomas.

The hst-1 gene, previously designated as the hst gene, and seven other oncogenes were examined for possible structural changes in esophageal, gastric and colorectal carcinomas by Southern blot hybridization. The hst-1 gene was amplified in eight (42.1%) of the nineteen esophageal squamous cell carcinomas and in all four metastatic tumors of lymph nodes. The degree of amplification ranged from two to eight times. Coamplification of the hst-1 and c-erbB-1 gene was found in one case of esophageal carcinoma. However, no amplification of the hst-1 gene was detected in gastric and colorectal carcinomas.

Adult↗
PubMed1988

Coamplification of the hst-1 and int-2 genes in human cancers.

The hst-1 gene, previously designated the hst gene, was identified as a transforming gene by transfection assays of genomic DNAs from various types of human cancers. We analyzed for alterations of the hst-1 gene in 18 bladder cancers, 23 renal cell carcinomas and 5 esophageal cancers. Although rearrangement of the gene was not detected in any of these samples, amplification of the hst-1 gene was found in 4 samples of tumors, including an invasive bladder cancer, both primary esophageal cancer and its lymph node metastasis, and kidney metastasis of an esophageal cancer. The same degree of amplification of the int-2 gene, the product of which has significant homology with the hst-1-encoded protein, was also observed in all of these DNA samples with amplified hst-1 gene. This result indicates close chromosomal localization of the two genes, which were amplified as one amplification unit.

Cell Line↗