Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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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 Vol. 75 ( 2 ) page： 239 - 248 1996.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Vol. 75 ( 2 ) page： 239 - 248 1996.8

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 Vol. 75 ( 2 ) page： 239 - 48 1996.8

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

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

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 329 ( 1 ) page： 39 - 46 1996.5

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 Vol. 329 ( 1 ) page： 39 - 46 1996.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Vol. 65 ( 4 ) page： 437 - 441 1996.2

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 Vol. 65 ( 4 ) page： 437 - 441 1996.2

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

Scopus

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

OKAMOTO K.

Int. J. Cancer Vol. 65 ( 4 ) page： 437 - 441 1996.2

Oxidative stress response in iron-induced acute nephrotoxicity: Enhanced expression of heat shock protein 90 Reviewed International journal

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

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 219 ( 1 ) page： 76 - 81 1996.2

Oxidative stress response in iron-induced acute nephrotoxicity: Enhanced expression of heat shock protein 90

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

Biochemical and Biophysical Research Communications Vol. 219 ( 1 ) page： 76 - 81 1996.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications

Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we determined the proteins preferentially produced in response to the Fe-NTA-induced oxidative injury. A single intraperitoneal Fe-NTA treatment led to the enhanced production of a number of proteins with molecular masses of 85-95 kDa. These included heat shock protein 90 (HSP90) as determined by immunoprecipitation. The enhanced production of HSP90 was prominent in the renal tubular cells. Steady accumulation of HSP90 was observed in the subacute toxicity experiments with multiple injections of Fe-NTA, suggesting that the enhanced production of HSP90 is important in increasing resistance to subsequent injury caused by the Fe-NTA-induced oxidative stress.

DOI： 10.1006/bbrc.1996.0184

Scopus

Association between 8-hydroxy-2'-deoxyguanosine formation and DNA strand breaks mediated by copper and iron

Toyokuni S, Sagripanti JL

FREE RADICAL BIOLOGY AND MEDICINE Vol. 20 ( 6 ) page： 859 - 864 1996

Iron-induced carcinogenesis: The role of redox regulation

Toyokuni S

FREE RADICAL BIOLOGY AND MEDICINE Vol. 20 ( 4 ) page： 553 - 566 1996

Iron-induced carcinogenesis: The role of redox regulation

Toyokuni S.

Free Radical Biology and Medicine Vol. 20 ( 4 ) page： 553 - 566 1996

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

Redox cycling is a characteristic of transition metals such as iron. Iron is hypothesized to have been actively involved in the birth of primitive life on earth through the generation of reducing equivalents in the presence of UV light. Iron is an essential metal in mammals for oxygen transport by hemoglobin and for the function of many enzymes including catalase and cytochromes. However, the 'free' or 'catalytic' form of iron mediates the production of reactive oxygen species via the Fenton reaction and induces oxidative stress. Serum 'free' iron is observed in rare situations such as in severe hemochromatosis in which serum transferrin is saturated. However, it is known that superoxide can release 'free' iron from ferritin and hemosiderin in the cell. 'Free' iron is quite cytotoxic as well as mutagenic and carcinogenic. Iron compounds were first reported to induce sarcomas in rats by Richmond in 1959. Thereafter, several iron-induced carcinogenesis models were established, including the ferric nitrilotriacetate model by Okada and colleagues. Iron may have a role in the carcinogenic process of other transition metals such as copper and nickel, or other kinds of carcinogens such as nitrosamine and even virus-induced carcinogenesis. In humans, genetic hemochromatosis and asbestosis are two major diseases associated with iron-induced carcinogenesis. There is an increasing number of reports of an association between increased body iron stores and increased risk of cancer. Iron-induced oxidative stress results in two possible consequences: (1) redox regulation failure that leads to lipid peroxidation and oxidative DNA and protein damage; (2) redox regulation that activates a variety of reducing and oxystress-protective mechanisms via signal transduction. Both consequences appear to play a role in iron-induced carcinogenesis.

DOI： 10.1016/0891-5849(95)02111-6

Scopus

Association between 8-hydroxy-2'-deoxyguanosine formation and DNA strand breaks mediated by copper and iron

TOYOKUNI S.

Free Radic. Biol. Med. Vol. 20 ( 6 ) page： 859 - 864 1996

8-Hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure

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

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Investigative Dermatology

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a mutation-prone (G:C to T:A transverion) DNA base-modified product generated by reactive oxygen species or photodynamic action. G:C to T:A transversions are observed in the p53 and ras genes of UVB-induced skin cancers of mice and in squamous and basal cell carcinomas of human skin exposed to sun-light. In the current study, 8-OHdG formation was evaluated in the epidermis of hairless mice after repeated exposure to UVB, and possible mechanisms involved were studied. Exposure of hairless mice to either 3.4 [2 minimal erythema dose (MED)] or 16.8 (10 MED) kJ/m2 of UVB three times a week for 2 wk induced a 2.5- or 6.1-fold increase, respectively, in the levels of 8-OHdG in DNA, compared to the unexposed controls. An immunohistochemical method using a monoclonal antibody specific for 8-OHdG showed stronger and more extensive staining in the nuclei of UV-irradiated epidermal cells than in those of nonirradiated cells. Western blots probed with antibodies against 4-hydroxy-2-nonenal-modified proteins confirmed the involvement of reactive oxygen species in the epidermal damage induced by chronic UVB exposure. 3-Nitro-L-tyrosine was detected in western blots in a concentration-dependent manner, suggesting that peroxynitrite derived from the reaction of nitric oxide and superoxide, both of which were probably released from inflammatory cells, was involved in modifying the DNA bases. Therefore, the formation of 8-OHdG after UVB exposure appears to be regulated by at least three pathways: photodynamic action, lipid peroxidation, and inflammation and may play a role in sunlight-induced skin carcinogenesis.

DOI： 10.1111/1523-1747.ep12365625

Scopus

Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies Reviewed International journal

Uchida K, Itakura K, Kawakishi S, Hiai H, Toyokuni S, Stadtman ER

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 324 ( 2 ) page： 241 - 248 1995.12

Characterization of epitopes recognized by 4-Hydroxy-2-nonenal specific antibodies

Uchida K., Itakura K., Kawakishi S., Hiai H., Toyokuni S., Stadtman E.

Archives of Biochemistry and Biophysics Vol. 324 ( 2 ) page： 241 - 248 1995.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Archives of Biochemistry and Biophysics

In the present study, we have raised anti-peptide antibodies directed to the major membrane lipid peroxidation product 4-hydroxy-2-nonenal (HNE) attached covalently to histidine, and their specificities were compared with those of the polyclonal antibodies (anti-HNE-protein antibodies) raised against HNE-treated keyhole limpet hemocyanin (K. Uchidaet al.(1993)Proc. Natl. Acad. Sci. USA90, 8742-8746). The anti-HNE-histidyl peptide antibodies (anti-HNE-histidine antibodies) were prepared by immunizing rabbits with a HNE-conjugated heptapeptide (Gly3-His-Gly3amide) coupled to the carrier protein. The antisera were purified on an affinity gel prepared by covalent attachment of a HNE-conjugated heptapeptide (Ala3-His-Ala3amide). Among the structurally defined 4-hydroxy-2-alkenal-amino acid adducts tested, binding of anti-HNE-histidine antibodies to the HNE-treated protein was not only inhibited by HNE-histidine, HNE-cysteine, and HNE-lysine, but also by 4-hydroxy-2-octenal-histidine and 4-hydroxy-2-decenal-histidine adducts. Cross-reactivity studies revealed that both anti-HNE-protein antibodies had the highest affinity for the HNE-treated protein and that neither of the antibodies cross-reacted with the protein treated with aldehydes including malondialdehyde, 1-hexanal, 2-hexenal, or 2-nonenal. These results suggest that the dominant epitope recognized by antibodies is the 2-CH3(CH2)n-5-hydroxytetrahydrofuran (n≥ 3) moiety of the Michael adducts. The immunohistochemical analysis of atherosclerotic lesions of human aorta demonstrated that these antibodies reacted strongly with granular cytoplasmic elements of foam cells and weakly with elements in the surrounding sclerotic stroma. © 1995 Academic Press. All rights reserved.

DOI： 10.1006/abbi.1995.0036

Scopus

Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies Reviewed International journal

Uchida K, Itakura K, Kawakishi S, Hiai H, Toyokuni S, Stadtman ER

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 324 ( 2 ) page： 241 - 248 1995.12

Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of Wistar rats induced by ferric nitrilotriacetate

Nishiyama Y, Suwa H, Okamoto K, Fukumoto M, Hiai H, Toyokuni S

JAPANESE JOURNAL OF CANCER RESEARCH Vol. 86 ( 12 ) page： 1150 - 1158 1995.12

Low Incidence of Point Mutations in H- ,K- and N-ras Oncogenes and p53 Tumor Suppressor Gene in Renal Cell Carcinoma and Peritoneal Mesothelioma of Wistar Rats Induced by Ferric Nitrilotriacetate

NISHIYAMA Yasuyuki, SUWA Hirofumi, OKAMOTO Keisei, FUKUMOTO Manabu, HIAI Hiroshi, TOYOKUNI Shinya

Jpn J Cancer Res Vol. 86 ( 12 ) page： 1150 - 1158 1995.12

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Papers - TOYOKUNI Shinya