Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Quantitative immunohistochemical determination of 8-hydroxy-2'-deoxyguanosine by a monoclonal antibody N45.1: Its application to ferric nitrilotriacetate-induced renal carcinogenesis model Reviewed International journal

Toyokuni S, Tanaka T, Hatton Y, Nishiyama Y, Yoshida A, Uchida K, Hiai H, Ochi H, Osawa T

LABORATORY INVESTIGATION Vol. 76 ( 3 ) page： 365 - 374 1997.3

Quantitative immunohistochemical determination of 8-hydroxy-2'- deoxyguanosine by a monoclonal antibody N45.1: Its application to ferric nitrilotriacetate-induced renal carcinogenesis model Reviewed International journal

Toyokuni S., Tanaka T., Hattori Y., Nishiyama Y., Yoshida A., Uchida K., Hiai H., Ochi H., Osawa T.

Laboratory Investigation Vol. 76 ( 3 ) page： 365 - 374 1997.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Laboratory Investigation

The DNA base-modified product 8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most commonly used markers for the evaluation of oxidative DNA damage. A monoclonal antibody specific for 8-OHdG (N45.1) was characterized end applied in quantitative immunohistochemistry. N45.1 recognized both the modified base and deoxyribose structure of 8-OHdG and required a concentration two orders higher of 8-hydroxyguanosine as a competitor in the ELISA. In addition, N45.1 did not cross-react with the original four deoxyribonucleosides, other DNA base-modified products such as 8-hydroxy-2'- deoxyadenosine and O6-methyl-2'-deoxyguanosine, or urine components such as uric acid, creatine, and creatinine. A ferric nitrilotriacetate-induced rat renal carcinogenesis model was used for the evaluation of quantitative immunohistochemistry. The 8-OHdG index of quantitative immunohistochemistry, as analyzed by NIH Image freeware, correlated reasonably well with the 8- OHdG amount determined by high-performance liquid chromatography with an electrochemical detector-except for a difference in peak time, which could be attributed to the selection of target location. The present method has advantages over the high-performance liquid chromatography/electrochemical detector, gas chromatography/mass spectrometry, and 32P-postlabeling methods in that it allows localization of 8-OHdG to be specified without the risk of artifactual production of 8-OHdG during the DNA extraction and hydrolytic processes.

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Quantitative immunohistochemical determination of 8-hydroxy-2'-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model.

Toyokuni S, Tanaka T, Hattori Y, Nishiyama Y, Yoshida A, Uchida K, Hiai H, Ochi H, Osawa T

Laboratory investigation; a journal of technical methods and pathology Vol. 76 ( 3 ) page： 365 - 74 1997.3

Overexpression of Integrin-associated Protein (CD47) in Rat Kidney Treated with a Renal Carcinogen, Ferric Nitrilotriacetate

NISHIYAMA Yasuyuki, TANAKA Tomoyuki, NAITOH Hiroshi, MORI Chisato, FUKUMOTO Manabu, HIAI Hiroshi, TOYOKUNI Shinya

Jpn, J. Cancer Res. Vol. 88 ( 2 ) page： 120 - 128 1997.2

Overexpression of Integrin-associated Protein (CD47) in Rat Kidney Treated with a Renal Carcinogen, Ferric Nitrilotriacetate

NISHIYAMA Yasuyuki, TANAKA Tomoyuki, NAITOH Hiroshi, MORI Chisato, FUKUMOTO Manabu, HIAI Hiroshi, TOYOKUNI Shinya

Japanese journal of cancer research : gann Vol. 88 ( 2 ) page： 120 - 128 1997.2

Induction of a wide range of C<inf>2-12</inf> aldehydes and C<inf>7-12</inf> acyloins in the kidney of wistar rats after treatment with a renal carcinogen, ferric nitrilotriacetate

Toyokuni S., Luo X.P., Tanaka T., Uchida K., Hiai H., Lehotay D.C.

Free Radical Biology and Medicine Vol. 22 ( 6 ) page： 1019 - 1027 1997.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Free Radical Biology and Medicine

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 C2-12 saturated and unsaturated aldehydes and C7-12 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.

DOI： 10.1016/S0891-5849(96)00489-3

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8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure (vol 107, pg 733, 1996)

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

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 108 ( 2 ) page： 237 - 237 1997.2

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

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

JAPANESE JOURNAL OF CANCER RESEARCH Vol. 88 ( 2 ) page： 120 - 128 1997.2

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 Reviewed International journal

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

FREE RADICAL BIOLOGY AND MEDICINE Vol. 22 ( 6 ) page： 1019 - 1027 1997

A case of malignant myoenithelioma in the hard palate

KITA Jun, IWAI Hiroshi, TOYOKUNI Shinya, YANAGIDA Masahiro, KAWASAKI Eiko, MINAMINO Masayuki, NAKASHIMA Yasuaki, YAMASHITA Toshio

OTOLOGIA FUKUOKA Vol. 43 ( 1 ) page： 30 - 33 1997

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：JIBI TO RINSHO KAI

A rare case of low grade malignant myoepithelioma arising from the hard palate is reported. The CT findings indicated a defect of the hard palate due to the tumor. Surgery combined with postoperative irradiation therapy was performed. A histopathological examination indicated that the tumor originated in the myoepithelial cells, invaded the hard palate, and also showed cellular atypia with rare mitoses. Malignant myoepithelioma clinically shows a low sensitivity to both radiation therapy and chemotherapy. Surgery should thus be the first choice of treatment.

DOI： 10.11334/jibi1954.43.1_30

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

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

Japanese Journal of Cancer Research Vol. 88 ( 2 ) page： 120 - 128 1997

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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

Scopus

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 Reviewed

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

FREE RADICAL BIOLOGY AND MEDICINE Vol. 22 ( 6 ) page： 1019 - 1027 1997

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

Web of Science

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

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

Laboratory Investigation Vol. 77 ( 2 ) page： 145 - 155 1997

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 Vol. 47 ( 4 ) page： 203 - 208 1997

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Reviewed International journal

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

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 107 ( 5 ) page： 733 - 737 1996.11

8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure Reviewed International journal

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

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 107 ( 5 ) page： 733 - 737 1996.11

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

Jpn J Cancer Res Vol. 87 ( 9 ) page： 882 - 886 1996.9

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 Vol. 87 ( 9 ) page： 882 - 886 1996.9

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

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

JAPANESE JOURNAL OF CANCER RESEARCH Vol. 87 ( 9 ) page： 882 - 886 1996.9

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 Vol. 87 ( 9 ) page： 882 - 886 1996.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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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Papers - TOYOKUNI Shinya