研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Development of high-grade renal cell carcinomas in rats independently of somatic mutations in the Tsc2 and VHL tumor suppressor genes

Toyokuni S, Okada K, Kondo S, Nishioka H, Tanaka T, Nishiyama Y, Hino O, Hiai H

JAPANESE JOURNAL OF CANCER RESEARCH 89 巻 ( 8 ) 頁： 814 - 820 1998年8月

A processed grain food inhibits hepatic injury in endotoxemic rats

Minamiyama Y, Takemura S, Toyokuni S, Tanimoto Y, Sato EF, Inoue M

JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY 44 巻 ( 4 ) 頁： 547 - 559 1998年8月

Development of high-grade renal cell carcinomas in rats independently of somatic mutations in the Tsc2 and VHL tumor suppressor genes

Toyokuni S., Okada K., Kondo S., Nishioka H., Tanaka T., Nishiyama Y., Hino O., Hiai H.

Japanese Journal of Cancer Research 89 巻 ( 8 ) 頁： 814 - 820 1998年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Cancer Research

Ferric nitrilotriacetate (Fe-NTA) induces renal proximal tubular damage that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. The RCCs are characterized by 1) high incidence of pulmonary metastasis and peritoneal invasion, 2) high incidence of tumor-associated mortality and 3) possible involvement of reactive oxygen species in carcinogenesis. The present study investigated the possible role of Tsc2 and VHL tumor suppressor genes in this model. Thirty-four Fe-NTA-induced primary RCCs and 20 other primary or metastatic tumors of rats were searched for genetic alteration in all the coding exons of both genes by polymerase chain reaction-single-strand-conformation polymorphism analysis and sequencing in conjunction with morphological evaluation. In the Fe-NTA-induced RCCs, frequency of metastasis or invasion was proportionally associated with the nuclear grade of the tumor (grades 1-3). Only one Fe-NTA-induced RCC of grade 1 revealed missense mutations with loss of heterozygosity in exon 10 of the Tsc2 gene (codons 334, GTG (Val) to GCG (Ala), and 336, TAT (Tyr) to CAT (His)). No mutation was found in the VHL gene. The results suggest that 1) high-grade RCCs can develop in the absence of mutations in the Tsc2 and VHL genes in rats, and that 2) Tsc2 gene somatic mutation can nonetheless be one of the causes of non-Eker rat RCCs.

DOI： 10.1111/j.1349-7006.1998.tb00633.x

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Development of high-grade renal cell carcinomas in rats independently of somatic mutations in the Tsc2 and VHL tumor suppressor genes

Toyokuni S, Okada K, Kondo S, Nishioka H, Tanaka T, Nishiyama Y, Hino O, Hiai H

JAPANESE JOURNAL OF CANCER RESEARCH 89 巻 ( 8 ) 頁： 814 - 820 1998年8月

Oxidative stress and cancer: The role of redox regulation

Toyokuni S.

Biotherapy 11 巻 ( 2-3 ) 頁： 147 - 154 1998年7月

Over-expression of glutathione S-transferase Yp isozyme and concomitant down-regulation of Ya isozyme in renal cell carcinoma of rats induced by ferric nitrilotriacetate 査読有り国際誌

Tanaka T, Nishiyama Y, Okada K, Satoh K, Fukuda A, Uchida K, Osawa T, Hiai H, Toyokuni S

CARCINOGENESIS 19 巻 ( 5 ) 頁： 897 - 903 1998年5月

Oxidative stress in pancreatic β-cells of GK rat, a model of non-obese NIDDM

Ihara, Y; Yamada, Y; Uchida, K; Toyokuni, S; Seino, Y

DIABETES 47 巻頁： A263 - A263 1998年5月

Oxidative stress in pancreatic beta-cells of GK rat, a model of non-obese NIDDM 国際誌

Ihara Y, Yamada Y, Uchida K, Toyokuni S, Seino Y

DIABETES 47 巻頁： A263 - A263 1998年5月

Over-expression of glutathione S-transferase Yp isozyme and concomitant down-regulation of Ya isozyme in renal cell carcinoma of rats induced by ferric nitrilotriacetate

Tanaka T., Nishiyama Y., Okada K., Satoh K., Fukuda A., Uchida K., Osawa T., Hiai H., Toyokuni S.

Carcinogenesis 19 巻 ( 5 ) 頁： 897 - 903 1998年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Carcinogenesis

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular damage, a consequence of iron-catalysed Fenton-like reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Glutathione S-transferase (GST) is a family of enzymes that play an important role in detoxification of hydrophobic and electrophilic molecules, and has been associated with putative preneoplastic foci of rat hepatocarcinogenesis and chemotherapy-resistance of human cancers. Our previous study revealed an induction of π-class glutathione S-transferase (Yp) mRNA in the kidney 3 h after administration of Fe-NTA. In the present study, expression of GST isozymes were further investigated in the Fe-NTA-induced RCCs of rats which are characterized by (1) high incidence of metastasis and invasion, (2) high incidence of tumour-associated mortality, and (3) possible involvement of reactive oxygen species in carcinogenesis. In the Fe-NTA-induced RCCs, the levels of α-class GST (Ya) mRNA and proteins were markedly decreased with no apparent change in the copy number of the gene. In contrast, GST-Yp mRNA and proteins were significantly increased in the RCCs while the total GST enzymatic activity was decreased. Immunohistochemical analysis revealed intense staining of GST-Yp not only in the primary RCCs and its metastatic sites, but also in their non-tumorous part of proximal tubules. The contrastive expression of GST isozymes in this renal carcinogenesis model suggests an alteration of its transcription mechanisms and warrants further investigation of this particular detoxifying enzyme from the viewpoint of reactive oxygen species-induced carcinogenesis.

DOI： 10.1093/carcin/19.5.897

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Immunohistochemical detection of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver diseases

Ohhira M, Ohtake T, Matsumoto A, Saito H, Ikuta K, Fujimoto Y, Ono M, Toyokuni S, Kohgo Y

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 22 巻 ( 3 ) 頁： 145S - 149S 1998年5月

Immunohistochemical detection of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver diseases 査読有り

M Ohhira, T Ohtake, A Matsumoto, H Saito, K Ikuta, Y Fujimoto, M Ono, S Toyokuni, Y Kohgo

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 22 巻 ( 3 ) 頁： 145S - 149S 1998年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

4-Hydroxy-2-nonenal (HNE) is one of the major components of lipid peroxidation product and has been shown to react with proteins to form HNE-protein adducts. HNE-protein adducts are relatively stable and can be used as a marker of radical-mediated cellular damage. We report herein the immunohistochemical analysis of HNE-protein adducts in human alcoholic liver diseases using a specific monoclonal antibody HNEJ-2. Cytoplasm of hepatocytes and bile duct epithelia was positively stained for HNE-protein adducts, and the nucleus was negligibly stained. The immunohistochemical intensity of hepatocytes was classified into three groups: strong, moderate, and faint staining. Strong staining was found in 43% of alcoholic liver diseases and in 4% of viral liver diseases. Hepatocytes of alcoholic liver diseases contained a higher amount of HNE-protein adducts than those of viral liver diseases, and the difference was statistically significant (p = 0.005; chi(2) test). Semiquantitative analysis of the histological intensities of HNE-protein adducts and iron indicated a significant positive correlation (p = 0.084; Spearman's rank correlation). The localization of HNE-protein adducts and iron in hepatocytes appeared to be identical. These data suggested the correlation between HNE-protein adducts and iron. Our results indicate that HNE-protein adducts, a marker of oxidative stress-induced damage, are increased in human alcoholic liver damage, and that hepatic siderosis may act on the production of free radicals.

DOI： 10.1111/acer.1998.22.s3_part1.145s

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Oxidative stress in pancreatic β-cells of GK rat, a model of non-obese NIDDM 国際誌

Ihara, Y, Yamada, Y, Uchida, K, Toyokuni, S, Seino, Y

DIABETES 47 巻頁： A263 - A263 1998年5月

Significant deposition of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver disease; Positive correlation with parenchymal iron. 国際誌 Open Access

Ohhira, M; Ohtake, T; Matsumoto, A; Saito, H; Kawashima, T; Ikuta, K; Tanaka, K; Fujimoto, Y; Ono, M; Toyokuni, S; Kohgo, Y

GASTROENTEROLOGY 114 巻 ( 4 ) 頁： A1315 - A1315 1998年4月

The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-OHdG in arsenic related Bowen's disease.

Matsui, M; Nishigori, C; Toyokuni, S; Takada, J; Akaboshi, M; Ochi, H; Ishikawa, M; Imamura, S

JOURNAL OF INVESTIGATIVE DERMATOLOGY 110 巻 ( 4 ) 頁： 526 - 526 1998年4月

The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-OHdG in arsenic related Bowen's disease. 国際誌 Open Access

Matsui, M, Nishigori, C, Toyokuni, S, Takada, J, Akaboshi, M, Ochi, H, Ishikawa, M, Imamura, S

JOURNAL OF INVESTIGATIVE DERMATOLOGY 110 巻 ( 4 ) 頁： 526 - 526 1998年4月

Enhanced hepatic lipid peroxidation in chronic hepatitis C 査読有り国際誌

Kageyama F., Kobayashi Y., Koide S., Murohisa G., Otake M., Shimizu E., Sasada Y., Suzuki F., Kawasaki T., Nakamura H., Toyokuni S., Uchida K.

Japanese Pharmacology and Therapeutics 26 巻 ( SUPPL. 2 ) 頁： 149 - 152 1998年4月

Enhanced hepatic lipid peroxidation in chronic hepatitis C 査読有り国際誌

Kageyama F, Kobayashi Y, Koide S, Murohisa G, Otake M, Shimizu E, Sasada Y, Suzuki F, Kawasaki T, Nakamura H, Toyokuni S, Uchida K

Japanese Pharmacology and Therapeutics 26 巻 ( SUPPL. 2 ) 頁： 149 - 152 1998年4月

Involvement of nitric oxide in survival of random pattern skin flap

Um SC, Suzuki S, Toyokuni S, Kim BM, Tanaka T, Hiai H, Nishimura Y

PLASTIC AND RECONSTRUCTIVE SURGERY 101 巻 ( 3 ) 頁： 785 - 792 1998年3月

Involvement of nitric oxide in survival of random pattern skin flap

Um S.C., Suzuki S., Toyokuni S., Kim B.M., Tanaka T., Hiai H., Nishimura Y.

Plastic and Reconstructive Surgery 101 巻 ( 3 ) 頁： 785 - 792 1998年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Plastic and Reconstructive Surgery

A free radical gas, nitric oxide, has many useful functions when produced under physiological conditions by neurons and endothelial cells. However, excess nitric oxide has been reported to exert cytotoxic effects by direct toxicity or by reaction with superoxide. The effect of nitric oxide on the microcirculation in the periphery of a flap remains unclear, and its effect on flap survival is also unknown because nitric oxide has a dual action. Thus, we attempted to clarify the effect of nitric oxide on survival of rat random pattern skin flaps by the use of an endothelial constitutive nitric oxide synthase inhibitor (IP administration of 50 mg/kg N(G)-nitro-L- arginine) and the substrate of nitric oxide synthase (IP administration of 1 g/kg L-arginine). Three kinds of experiments were done using a total number of 120 animals: (1) time course measurement of blood flow in the flap periphery was performed using a laser Doppler flowmeter (30 rats), (2) tile length of the surviving area of flaps was measured 1 week after raising the flap (60 rats), and (3) Western blot analysis was used to determine the time course of changes ill tile amount of endothelial constitutive nitric oxide synthase and the formation of 3-nitro-L-tyrosine, which is it marker of peroxynitrite-mediated (i.e., nitric oxide-dependent) tissue damage (30 rats). Inhibition of endothelial constitutive nitric oxide synthase by N(G)- nitro-L-arginine significantly decreased the length of the surviving area of skin flap (p < 0.01 compared with the control), which was associated with a decrease in tim blood flow of the proximal portion of the flap. On the other hand, exogenous L-arginine increased the survival length of skin flap significantly (p < 0.01 compared with the control), which was associated with all increase in blood flow of the distal portion of the flap even though there was nitric oxide-mediated oxidative tissue damage. These results suggest that nitric oxide produced by endothelial constitutive nitric oxide synthase plays a role in maintaining circulation in the skin flap periphery and that L-arginine administration contributes to reduction of ischemic necrosis in the skin flap.

DOI： 10.1097/00006534-199803000-00030

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CiNii Research

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Major targets of ROS-induced cancer in rats are p15/p16 oncosuppressor genes

Toyokuni, S; Tanaka, T; Iwasa, Y; Kondo, S; Hiai, H

FREE RADICAL BIOLOGY AND MEDICINE 25 巻頁： S119 - S119 1998年

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