研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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喜多淳, 岩井大, 豊國伸哉, 柳田昌宏, 川崎英子, 南野雅之, 中嶋安彬, 山下敏夫

耳鼻と臨床 43 巻 ( 1 ) 頁： 30 - 33 1997年

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：JIBI TO RINSHO KAI

硬口蓋に原発した極めて稀な小唾液腺由来の悪性筋上皮腫の症例を経験した. 病理組織学的に筋上皮細胞由来であり, 悪性である細胞分裂像に乏しい点で低悪性型筋上皮腫と診断した. 手術的摘出と術後の放射線照射を行った.<BR>性筋上皮腫はこれまでの報告例がなく, 治療方針は定まつていないのが現状であるが, 一般の扁平上皮癌に比し放射線療法や化学療法の効果が低いことは, 他の腺系悪性腫瘍と同様の性状であると思われる. したがつて, 放射線療法や化学療法はあくまで補助的な治療であり, 手術的摘出が優先されると思われる.

DOI： 10.11334/jibi1954.43.1_30

CiNii Research

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Overexpression of integrin-associated protein (CD47) in rat kidney treated with renal carcinogen, ferric nitrilotriacetate Open Access

Nishiyama Y., Tanaka T., Naitoh H., Mori C., Fukumoto M., Hiai H., Toyokuni S.

Japanese Journal of Cancer Research 88 巻 ( 2 ) 頁： 120 - 128 1997年

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

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis, a consequence of free radical-associated damage, that ultimately leads to a polycystic change of the renal cortex and a high incidence of renal cell carcinoma (RCC) in rodents. The differential display technique was used to search for inducible genes in the kidney of male Wistar rats treated with Fe-NTA and in the induced RCCs. Six fragments were selected that showed specific quantitative changes in mRNA. Two of them exhibited similar patterns in northern blots as well. One fragment showed a high homology (89%) to murine integrin-associated protein (IAP; CD47). We thus cloned rat IAP cDNA including the entire coding region for use in further analysis. Rat IAP cDNA showed a 21-amino-acid deletion that was also observed in human, but not in mouse. Northern blots revealed that IAP was consistently overexpressed in non-tumorous parts of the kidney (2.4-fold increase, n = 9, P < 0.0001) as compared with matched controls 1 to 2 years after Fe-NTA treatment. IAP overexpression of more than 2.9-fold was found in 25% (2/8) of RCCs studied, and was limited to cases of a high histological grade and lung metastasis. Unexpectedly, IAP expression was higher in the non-tumorous part of the kidney after Fe-NTA treatment (2.8-fold) than in RCC (1.5-fold) in each case (n = 4, P < 0.05). Abundant expression of IAP mRNA in the renal tubular epithelium after Fe-NTA treatment and RCC cells was observed by in situ hybridization. The results suggest that IAP overexpression may be associated with Fe-NTA-induced renal cortical tubular damage and regeneration that lead to a polycystic state, and with tumor progression and metastasis of the induced RCCs.

DOI： 10.1111/j.1349-7006.1997.tb00356.x

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Induction of a wide range of C-2-12 aldehydes and C-7-12 acyloins in the kidney of Wistar rats after treatment with a renal carcinogen, ferric nitrilotriacetate 査読有り

S Toyokuni, XP Luo, T Tanaka, K Uchida, H Hiai, DC Lehotay

FREE RADICAL BIOLOGY AND MEDICINE 22 巻 ( 6 ) 頁： 1019 - 1027 1997年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis associated with lipid peroxidation and oxidative DNA damage that finally leads to a high incidence of renal cell carcinoma in rodents. In the present study, we investigated what kinds of C-2-12 saturated and unsaturated aldehydes and C-7-12 acyloins, metabolites of saturated aldehydes, are produced in the kidney and liver within 24 h after single ip administration of 15 mg Fe/kg of Fe-NTA, or after repeated (1 or 3 wk) ip administration of 5-10 mg Fe/kg of Fe-NTA. Amounts of twenty one aldehydes and five acyloins were determined by capillary column gas chromatography-negative-ion chemical ionization mass spectrometry with ammonia as reagent gas. Most of the aldehydes and all the acyloins measured revealed a significant dose-dependent increase 1 to 3 h after single administration in the kidney, among which 4-hydroxy-2-nonenal (HNE) showed the highest increase (27.3-fold) and malondialdehyde (MDA) was the most abundant aldehyde (2.40 nmol/100 mg wet tissue). In the liver, however, the increase in aldehydes and acyloins was less prominent. After repeated administration of Fe-NTA, only 9 aldehydes (ethanal; furfural; trans,trans-2,4-heptadienal; nonanal; trans-2,cis-6-nonadienal; HNE; decanal; trans-4,cis-4-decenal; MDA) and 4 acyloins (3-hydroxyheptan-2-one; 3-hydroxyoctan-2-one; 3-hydroxynonan-2-one; 3-hydroxydodecan-2-one) showed a significant increase. Immunohistochemistry further demonstrated an increased amount of HNE-modified and MDA-modified proteins in the renal proximal tubules after repeated Fe-NTA administration. Some of the aldehydes measured such as HNE and MDA are reportedly cytotoxic, genotoxic and mutagenic. Accumulation of these aldehydes may play a role in this renal carcinogenesis model. Copyright (C) 1997 Elsevier Science Inc.

DOI： 10.1016/S0891-5849(96)00489-3

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Induction and nuclear translocation of thioredoxin by oxidative damage in the mouse kidney: Independence of tubular necrosis and sulfhydryl depletion 査読有り

Tanaka T, Nishiyama Y, Okada K, Hirota K, Matsui M, Yodoi J, Hiai H, Toyokuni S

Laboratory Investigation 77 巻 ( 2 ) 頁： 145 - 155 1997年

Copper and iron-induced oxidative damage in non-tumor bearing LEC rats

Ma Y., Zhang D., Kawabata T., Kiriu T., Toyokuni S., Uchida K., Okada S.

Pathology International 47 巻 ( 4 ) 頁： 203 - 208 1997年

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：Pathology International

The copper and iron status in the liver of non-tumor bearing Long-Evans Cinnamon (LEC) rats (average age 17 months) was investigated. A direct quantitation of loosely-bound copper and iron was also investigated by using a chelating agent, nitrilotriacetic acid (NTA-chelatable free copper and iron). Besides the total copper and iron contents, the level of NTA- chelatable free copper was also higher in LEC rats than in LEA rats (P<0.05). But for the free iron level there was no significant difference between the two rat groups (P>0.05). The formation of thiobarbituric acid-reactive substances was higher in LEC rate than in LEA rats (P<0.01). The 4-hydroxy- 2-nonenal (HNE)-modified proteins were also clearly demonstrated In LEC rat liver. The copper and iron which produced the most important effect in the process of oxidative damage in LEC rats could not be distinguished. Even though free copper, which could induce free radical injuries, was increased in LEC rats, neither tumor-induction nor preneoplastic lesions in the experimental LEC rats were observed. Therefore it is speculated that the elevation of s free iron is another important factor. Copper and iron, both important transition metals in the body, may participate in the induction of DNA damage and oncogenesis.

DOI： 10.1111/j.1440-1827.1997.tb04481.x

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8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure 査読有り国際誌

Hattori Y, Nishigori C, Tanaka T, Uchida K, Nikaido O, Osawa T, Hiai H, Imamura S, Toyokuni S

JOURNAL OF INVESTIGATIVE DERMATOLOGY 107 巻 ( 5 ) 頁： 733 - 737 1996年11月

8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure 査読有り国際誌

Hattori Y, Nishigori C, Tanaka T, Uchida K, Nikaido O, Osawa T, Hiai H, Imamura S, Toyokuni S

JOURNAL OF INVESTIGATIVE DERMATOLOGY 107 巻 ( 5 ) 頁： 733 - 737 1996年11月

Prevention by 2-Mercaptoethane Sulfonate and N-Acetylcysteine of Renal Oxidative Damage in Rats Treated with Ferric Nitrilotriacetate

UMEMURA Takashi, HASEGAWA Ryuichi, SAI-KATO Kimie, NISHIKAWA Akiyoshi, FURUKAWA Fumio, TOYOKUNI Shinya, UCHIDA Koji, INOUE Tohru, KUROKAWA Yuji

Japanese journal of cancer research : gann 87 巻 ( 9 ) 頁： 882 - 886 1996年9月

Prevention by 2-Mercaptoethane Sulfonate and N-Acetylcysteine of Renal Oxidative Damage in Rats Treated with Ferric Nitrilotriacetate

UMEMURA Takashi, HASEGAWA Ryuichi, SAI-KATO Kimie, NISHIKAWA Akiyoshi, FURUKAWA Fumio, TOYOKUNI Shinya, UCHIDA Koji, INOUE Tohru, KUROKAWA Yuji

Japanese journal of cancer research : gann 87 巻 ( 9 ) 頁： 882 - 886 1996年9月

Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate 査読有り国際誌

Umemura T, Hasegawa R, SaiKato K, Nishikawa A, Furukawa F, Toyokuni S, Uchida K, Inoue T, Kurokawa Y

JAPANESE JOURNAL OF CANCER RESEARCH 87 巻 ( 9 ) 頁： 882 - 886 1996年9月

Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate

Umemura T., Hasegawa R., Sai-Kato K., Nishikawa A., Furukawa F., Toyokuni S., Uchida K., Inoue T., Kurokawa Y.

Japanese Journal of Cancer Research 87 巻 ( 9 ) 頁： 882 - 886 1996年9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) is a renal toxicant and carcinogen in rats and mice. We found that its administration results in formation of 4-hydroxy-2-nonenal (HNE) in the renal proximal tubule cells of rats, and 8-hydroxydeoxyguanosine (8-OHdG) adducts in their DNA, suggesting a role for oxidative stress. Since 2-mercaptoethane sulfonate (MESNA) and N-acetylcysteine (NAC), administered orally, have been shown to increase the kidney levels of free thiol groups, their influence on the renal toxicity and carcinogenicity induced by Fe-NTA was examined in the present study. Male Wistar rats were intraperitoneally injected with Fe-NTA (12 mg Fe/kg), and MESNA (100 mg/kg) or NAC (200 mg/kg) was given orally 1 h before and 1 h after this treatment. The animals were killed for tissue analyses 3 h after the Fe-NTA exposure. In accord with our previous reports, HNE-modified protein was detected in the proximal tubules of Fe-NTA-treated rats by means of immunohistochemistry. Likewise, levels of 8-OHdG in the renal nuclear DNA, lipid peroxides as thiobarbituric acid-reactive substances in the kidneys, and blood urea nitrogen and creatinine in the serum were significantly increased by the Fe-NTA treatment. All of these changes were completely inhibited by oral administration of MESNA or NAG. These results suggest that both of these compounds can prevent the oxidative stress induced by Fe-NTA.

DOI： 10.1111/j.1349-7006.1996.tb02115.x

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Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate 査読有り国際誌

Umemura T, Hasegawa R, SaiKato K, Nishikawa A, Furukawa F, Toyokuni S, Uchida K, Inoue T, Kurokawa Y

JAPANESE JOURNAL OF CANCER RESEARCH 87 巻 ( 9 ) 頁： 882 - 886 1996年9月

Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate

Toyokuni S, Tanaka T, Nishiyama Y, Okamoto K, Nakashima Y, Hamazaki S, Okada S, Hiai H

LABORATORY INVESTIGATION 75 巻 ( 2 ) 頁： 239 - 248 1996年8月

Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate 査読有り国際誌

Toyokuni S., Tanaka T., Nishiyama Y., Okamoto K., Nakashima Y., Hamazaki S., Okada S., Hiai H.

Laboratory Investigation 75 巻 ( 2 ) 頁： 239 - 248 1996年8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：Laboratory Investigation

Systemic administration of copper, an essential trace metal in the human body, has never been reported to be carcinogenic in animals. We investigated the induction of tumors by the cupric complex of nitrilotriacetic acid (Cu- NTA) in male Wistar rats. Thirty-two animals received ip injections of Cu- NTA, 3 to 5 mg of copper/kg body weight 5 days a week for 12 weeks, and were kept under close observation. For comparison, 31 animals received ip injections of ferric nitrilotriacetate (Fe-NTA), 5 to 10 mg of iron/kg body weight, and 16 animals received nitrilotriacetic acid (NTA) alone at the molar dose equivalent to Cu-NTA for the same period of time. Sixteen animals were left untreated as controls. Fourteen animals in the Cu-NTA group died of hepatic failure during the treatment period, and renal cell carcinoma (RCC) was induced in eight animals (25%). Of these, four animals died of either pulmonary metastasis or intraperitoneal hemorrhage. A total of 12 RCC were obtained, of which six tumors were ≤5 mm. The Cu-NTA group yielded fewer RCC and required a longer latent period for their incubation than the Fe-NTA group. Furthermore, the Cu-NTA group showed one hepatocellular carcinoma and one high-grade sarcoma of hepatic origin. No renal or hepatic tumor was observed in the NTA or control groups. The nontumorous part of the kidney treated with Cu-NTA presented hemosiderosis caused by copper-induced hemolytic anemia. This is the first report that systemic administration of copper compounds can induce malignant tumors in animals. Not only copper but also iron may play a role in the Cu-NTA-induced renal carcinogenesis model.

Scopus

Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate

Toyokuni S, Tanaka T, Nishiyama Y, Okamoto K, Nakashima Y, Hamazaki S, Okada S, Hiai H

LABORATORY INVESTIGATION 75 巻 ( 2 ) 頁： 239 - 248 1996年8月

Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate.

Toyokuni S, Tanaka T, Nishiyama Y, Okamoto K, Nakashima Y, Hamazaki S, Okada S, Hiai H

Laboratory investigation; a journal of technical methods and pathology 75 巻 ( 2 ) 頁： 239 - 48 1996年8月

Oxidative stress response in iron-induced renal carcinogenesis: Acute nephrotoxicity mediates the enhanced expression of glutathione S-transferase Yp isozyme 査読有り国際誌

Fukuda A, Osawa T, Oda H, Toyokuni S, Satoh K, Uchida K

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 329 巻 ( 1 ) 頁： 39 - 46 1996年5月

Oxidative stress response in iron-induced renal carcinogenesis: Acute nephrotoxicity mediates the enhanced expression of glutathione S-transferase Yp isozyme

Fukuda A., Osawa T., Oda H., Toyokuni S., Satoh K., Uchida K.

Archives of Biochemistry and Biophysics 329 巻 ( 1 ) 頁： 39 - 46 1996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：Archives of Biochemistry and Biophysics

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces acute renal proximal tubular necrosis, a consequence of free radical-mediated oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we investigated the free radical-induced oxidative stress response in this carcinogenesis model, focusing on the expression of glutathione S-transferases (GSTs) which catalyze the conjugation of reactive chemicals with glutathione and play an important role in protecting cells. A single intraperitoneal Fe-NTA treatment (15 mg Fe/kg body weight) induced a rapid oxidative stress, which was monitored by the accumulation of lipid peroxidation products and the loss of sulfhydryl contents in the kidneys, resulting in a 30% reduction of GST activity 1 h after an Fe-NTA treatment. The enzyme activity returned to the control level after 16 h. The immunoblot analysis of GST isozymes demonstrated that the level of α-class GSTs (GST-Ya and GST-Yc) and π- class GST (GST-Yp), major GST isozymes constitutively produced in the kidney, decreased immediately within 1 h of the Fe-NTA treatment. The onset of the recovery of GST-Yp protein levels was detected 3 h after the Fe-NTA treatment. The enhanced production of GST-Yp in gene expression was evident in the drastic elevation of mRNA levels and these increases coincided with a substantial rise in the GST activity and protein levels. The α-class GSTs were not inducible by treatment with Fe-NTA. The immunohistochemical analysis demonstrated that the expression of GST-Yp was strongly induced in the regenerating proximal tubular cells. A steady accumulation of GST-Yp protein was observed in the subacute toxicity experiments with multiple injections of Fe-NTA. These results suggest that the enhanced expression of GST-Yp is important in mediating cell repairs or increasing the resistance to subsequent injury.

DOI： 10.1006/abbi.1996.0189

Scopus

Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer

Okamoto K, Toyokuni S, Kim WJ, Ogawa O, Kakehi Y, Arao S, Hiai H, Yoshida O

INTERNATIONAL JOURNAL OF CANCER 65 巻 ( 4 ) 頁： 437 - 441 1996年2月

Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer

Okamoto K., Toyokuni S., Kim W., Ogawa O., Kakehi Y., Arao S., Hiai H., Yoshida O.

International Journal of Cancer 65 巻 ( 4 ) 頁： 437 - 441 1996年2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：International Journal of Cancer

Data regarding oxidatively modified DNA bases suggest that cancer cells are more exposed to oxidative stress than adjacent non-tumorous tissue. This novel concept may contribute to the understanding of certain aspects of tumor biology such as activated transcription factors, genetic instability, chemotherapy resistance and metastasis. We therefore tested this concept in human renal-cell carcinomas (RCCs) by evaluating the expression of hMTHI, an enzyme preventing the misincorporation into DNA of 8-oxo-dGTP (8-oxo-7,8 -dihydrodeoxyguanosine triphosphate), an oxidized form of dGTP in the nucleotide pool. The expression of hMTHI messenger RNA (mRNA) in RCC was significantly higher than that in adjacent nontumorous kidney. Moreover, advanced-stage tumors showed significantly higher hMTHI mRNA expression than early-stage tumors, and there was a modest linear correlation between hMTHI expression and c-myc expression. The results provide logical support for the concept of 'persistent oxidative stress in cancer' and suggest a role of hMTHI mRNA level as prognostic marker.

DOI： 10.1002/(SICI)1097-0215(19960208)65:4<437::AID-IJC7>3.0.CO;2-Y

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