Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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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

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 damage, a consequence of iron-catalyzed free radical reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Previous studies have identified, within 24 h after administration of Fe-NTA, lipid peroxidation products, aldehyde-modified proteins and a variety of modified DNA bases such as 8-hydroxyguanine that may be mutagenic in vivo. In the present study, pathological features of the RCCs were studied, and, in an effort to correlate them with carcinogen-specific molecular events in Fe-NTA-induced carcinogenesis, the H-, K- and N-ras oncogenes and the p53 tumor suppressor gene were investigated for the presence of mutations. Fe-NTA-induced RCCs showed similarity to human RCCs in that they are often invasive, metastatic and fatal. None (0 of 12) of the tumors had mutation in codons 12,13 and 61 of the H-, K- and N-ras genes by direct sequencing. Only one (1 of 12) tumor with high grade histology revealed a CGC-to-CTC (Arg to Leu) transversion in codon 246 of the p53 gene by the use of single strand conformation polymorphism (SSCP) analysis and direct sequencing. High expression of mutant p53 protein was confirmed by Western blotting and immunohistochemistry. Study of three peritoneal mesotheliomas induced by Fe-NTA revealed no mutation in ras and p53 genes. These results suggest that the ras and p53 genes are not the major targets of mutation in Fe-NTA-induced carcinogenesis of kidney and mesothelium. Instead, p53 mutation may work for potentiation of malignant character in Fe-NTA-induced renal carcinogenesis. © 1995.

DOI： 10.1016/0910-5050(96)85255-0

Scopus

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

TREATMENT OF WISTAR RATS WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE, CAUSES DNA-PROTEIN CROSS-LINKING BETWEEN THYMINE AND TYROSINE IN THEIR RENAL CHROMATIN

TOYOKUNI S, MORI T, HIAI H, DIZDAROGLU M

INTERNATIONAL JOURNAL OF CANCER Vol. 62 ( 3 ) page： 309 - 313 1995.7

Treatment of wistar rats with a renal carcinogen, ferric nitrilotriacetate, causes dna‐protein cross‐linking between thymine and tyrosine in their renal chromatin

Toyokuni S., Mori T., Hiai H., Dizdaroglu M.

International Journal of Cancer Vol. 62 ( 3 ) page： 309 - 313 1995.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：International Journal of Cancer

Ferric nitrilotriacetate (Fe‐NTA) induces renal proximal tubular damage associated with lipid peroxidation and oxidative DNA base modifications that finally leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we report on the in vivo formation of DNA‐protein cross‐links (DPCs) involving thymine and tyrosine in the renal chromatin of Wistar rats treated with single or repeated i.p. administration of Fe‐NTA. Analyses of chromatin samples by gas chromatography/mass spectrometry revealed a significant increase in the amount of 3‐[(1, 3‐dihydro‐2, 4‐dioxopyrimidin‐5‐yl)‐methyl]‐L‐tyrosine (Thy‐Tyr cross‐link) 24 and 48 hr after the administration of Fe‐NTA. At 19th day of Fe‐NTA treatment, the amount of Thy‐Tyr cross‐link decreased to the control level, indicating the presence of cellular repair activity. Thy‐Tyr cross‐link may play a role in the genetic alteration of this renal carcinogenesis model, since mitoses for regeneration of renal proximal tubules were closely associated with the increase in DPCs. © 1995 Wiley‐Liss Inc. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910620313

Scopus

Treatment of Wistar rats with a renal carcinogen, ferric nitrilotriacetate, causes DNA-protein cross-linking between thymine and tyrosine in their renal chromatin

TOYOKUNI S.

Int J Cancer. Vol. 62 ( 3 ) page： 309 - 313 1995.7

4-HYDROXY-2-NONENAL-TRAPPING ELISA - DIRECT EVIDENCE FOR THE RELEASE OF A CYTOTOXIC ALDEHYDE FROM OXIDIZED LOW-DENSITY LIPOPROTEINS Reviewed International journal

UCHIDA K, OSAWA T, HIAI H, TOYOKUNI S

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 212 ( 3 ) page： 1068 - 1073 1995.7

DEGRADATION OF DNA IN DRIED TISSUES BY ATMOSPHERIC OXYGEN

MATSUO S, TOYOKUNI S, OSAKA M, HAMAZAKI S, SUGIYAMA T

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 208 ( 3 ) page： 1021 - 1027 1995.3

Degradation of DNA in dried tissues by atmospheric oxygen

Matsuo S., Toyokuni S., Osaka M., Hamazaki S., Sugiyama T.

Biochemical and Biophysical Research Communications Vol. 208 ( 3 ) page： 1021 - 1027 1995.3

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

Recently, DNA of extinct creatures have been brought into analyses. The difficulty in this field of research is DNA degradation. Oxidative damage is considered to be one of the causes of the DNA degradation. We studied how DNA in dried tissue was affected by atmospheric oxygen using freeze-dried rat liver as a model. In tissues exposed to oxygen, DNA degradation occurred within several months and the amount of 8-hydroxy-2′-deoxyguanosine in DNA rapidly increased. The DNA degradation was inhibited by lipid extraction prior to the exposure to atmospheric oxygen. Purified lambda phage DNA was not affected by oxygen. Cellular DNA and RNA were degraded slowly in nitrogen air. These results suggest that both atmospheric and endogenous oxygens play a role in DNA degradation in dried tissues. © 1995 Academic Press, Inc.

DOI： 10.1006/bbrc.1995.1436

Scopus

Degradation of DNA in dried tissues by atmospheric oxygen

MATSUO S.

Biochem Biophys Res Commun Vol. 208 ( 3 ) page： 1021 - 1027 1995.3

A RENAL CARCINOGEN FERRIC NITRILOTRIACETATE MEDIATES A TEMPORARY ACCUMULATION OF ALDEHYDE-MODIFIED PROTEINS WITHIN CYTOSOLIC COMPARTMENT OF RAT-KIDNEY Reviewed International journal

UCHIDA K, FUKUDA A, KAWAKISHI S, HIAI H, TOYOKUNI S

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 317 ( 2 ) page： 405 - 411 1995.3

A Renal carcinogen ferric nitrilotriacetate mediates a temporary accumulation of aldehyde-modified proteins within cytosolic compartment of rat-Kidney

Uchida K., Fukuda A., Kawakishi S., Hiai H., Toyokuni S.

Archives of Biochemistry and Biophysics Vol. 317 ( 2 ) page： 405 - 411 1995.3

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

Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. A recent immunohistochemical study has revealed that the materials immunoreactive to the antibody against the aldehyde (4-hydroxy-2-nonenal)-modified proteins are generated in the renal proximal tubules of rats treated with Fe-NTA (S. Toyokuni et al. (1994) Proc. Natl. Acad. Sci. USA 91, 2616-2620). Here we present further evidences that cytosolic proteins modified with lipid peroxidation-derived aldehydes (4-hydroxy-2-nonenal and malondialdehyde) are indeed accumulated in the kidney of rats treated with Fe-NTA. A single intraperitoneaI Fe-NTA treatment (15 or 30 mg Fe/kg body wt) induced a rapid accumulation of thiobarbituric acid-reactive substances, a direct consequence of membrane lipid peroxidation, mostly within the cytosolic compartment of rat kidney. The accumulation of lipid peroxidation-derived aldehydes was associated with an apparent accumulation (from 67.9 nmol in untreated controls to 83.3 nmol/mg protein in Fe-NTA-treated rats at 3 h after treatment) and subsequent elimination of aberrant proteins as assessed by a 2, 4-dinitrophenylhydrazine postlabeling assay. Immunoblot analysis with two different polyclonal antibodies against 4-hydroxy-2-nonenal-modified and malondialdehyde-modified proteins detected a temporary accumulation of aldehyde-modified proteins in the cytosol. An immunohistochemical technique with serial sectioning revealed that immunoreactivities of these antibodies were observed in the identical portion of the renal proximal tubules. The implications of these data in relation to the nephrotoxicity of Fe-NTA-are discussed. © 1995 Academic Press. All rights reserved.

DOI： 10.1006/abbi.1995.1181

Scopus

A RENAL CARCINOGEN FERRIC NITRILOTRIACETATE MEDIATES A TEMPORARY ACCUMULATION OF ALDEHYDE-MODIFIED PROTEINS WITHIN CYTOSOLIC COMPARTMENT OF RAT-KIDNEY Reviewed

K UCHIDA, A FUKUDA, S KAWAKISHI, H HIAI, S TOYOKUNI

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 317 ( 2 ) page： 405 - 411 1995.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS

Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. A recent immunohistochemical study has revealed that the materials immunoreactive to the antibody against the aldehyde (4-hydroxy-2-nonenal)-modified proteins are generated in the renal proximal tubules of rats treated with Fe-NTA (S. Toyokuni et al. (1994) Proc. Natl. Acad. Sci. USA 91, 2616-2620). Here we present further evidences that cytosolic proteins modified with lipid peroxidation-derived aldehydes (4-hydroxy-2-nonenal and malondialdehyde) are indeed accumulated in the kidney of rats treated with Fe-NTA. A single intraperitoneaI Fe-NTA treatment (15 or 30 mg Fe/kg body wt) induced a rapid accumulation of thiobarbituric acid-reactive substances, a direct consequence of membrane lipid peroxidation, mostly within the cytosolic compartment of rat kidney. The accumulation of lipid peroxidation-derived aldehydes was associated with an apparent accumulation (from 67.9 nmol in untreated controls to 83.3 nmol/mg protein in Fe-NTA-treated rats at 3 h after treatment) and subsequent elimination of aberrant proteins as assessed by a 2,4-dinitrophenylhydrazine postlabeling assay. Immunoblot analysis with two different polyclonal antibodies against 4-hydroxy-2-nonenal-modified and malondialdehyde-modified proteins detected a temporary accumulation of aldehyde-modified proteins in the cytosol. An immunohistochemical technique with serial sectioning revealed that immunoreactivities of these antibodies were observed in the identical portion of the renal proximal tubules. The implications of these data in relation to the nephrotoxicity of Fe-NTA-are discussed. (C) 1995 Academic Press, Inc.

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THE MONOCLONAL-ANTIBODY SPECIFIC FOR THE 4-HYDROXY-2-NONENAL HISTIDINE ADDUCT Reviewed International journal

TOYOKUNI S, MIYAKE N, HIAI H, HAGIWARA M, KAWAKISHI S, OSAWA T, UCHIDA K

FEBS LETTERS Vol. 359 ( 2-3 ) page： 189 - 191 1995.2

The monoclonal antibody specific for the 4-hydroxy-2-nonenal histidine adduct

Toyokuni S., Miyake N., Hiai H., Hagiwara M., Kawakishi S., Osawa T., Uchida K.

FEBS Letters Vol. 359 ( 2-3 ) page： 189 - 191 1995.2

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

Monoclonal antibodies directed against proteins modified with the major membrane lipid peroxidation product, 4-hydroxy-2-nonenal, have been established and characterized. The monoclonal antibodies specific for HNE-modified proteins were raised by immunizing mice with a HNE-keyhole limpet hemocyanin conjugate. The resulting five monoclonal antibodies (mAbs HNEJ-1-5) recognized HNE-modified bovine serum albumin (BSA), but not native BSA in Western blot studies. Of the five mAbs, HNEJ-2 exhibited the highest affinity for HNE-modified proteins and a much higher affinity for the HNE-histidine adduct than the HNE-lysine or HNE-cysteine adducts. mAb HNEJ-2 did not cross-react with proteins that had been treated with other aldehydes, such as 1-hexenal, 2-hexenal, 4-hydroxy-2-hexenal, 2-nonenal, formaldehyde, or glutaraldehyde. These results suggest that the major epitope recognized by mAb HNEJ-2 is the Michael addition-type HNE-histidine adduct. © 1995.

DOI： 10.1016/0014-5793(95)00033-6

Scopus

CYTOTOXIC AND MUTAGENIC EFFECTS OF FERRIC NITRILOTRIACETATE ON L5178Y MOUSE LYMPHOMA-CELLS

TOYOKUNI S, SAGRIPANTI JL, HITCHINS VM

CANCER LETTERS Vol. 88 ( 2 ) page： 157 - 162 1995.1

Cytotoxic and mutagenic effects of ferric nitrilotriacetate on L5178Y mouse lymphoma cells

TOYOKUNI S.

Cancer Lett. Vol. 88 ( 2 ) page： 157 - 162 1995.1

Cytotoxic and mutagenic effects of ferric nitrilotriacetate on L5178Y mouse lymphoma cells

Toyokuni S., Sagripanti J., Hitchins V.

Cancer Letters Vol. 88 ( 2 ) page： 157 - 162 1995.1

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

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis that leads to a high incidence of renal adenocarcinoma in rodents. Others have shown that Fe-NTA induces modified DNA base products both in vitro and in vivo. However, Fe-NTA is negative in the Ames Salmonella test with or without S9 activation. The goal of this project was to determine if Fe-NTA is cytotoxic and mutagenic using the L5178Y (TK+/-) mouse lymphoma assay. Our experiments showed a relationship between the concentration of Fe-NTA (0 to 1 mM) and the decrease in relative survival. An exposure-dependent increase in the number of mutations was observed with increasing concentrations of Fe-NTA. At 14% relative survival, there was about a 4-fold increase in mutations (trifluorothymidine resistance) over unexposed, control cells. Ferric nitrate or nitrilotriacetic acid alone induced a relatively tow 1.5- or 1.1-fold increase in mutation, respectively. Our results establish that Fe-NTA is mutagenic in the L5178Y mouse lymphoma assay system. © 1995.

DOI： 10.1016/0304-3835(94)03641-U

Scopus

PERSISTENT OXIDATIVE STRESS IN CANCER

TOYOKUNI S, OKAMOTO K, YODOI J, HIAI H

FEBS LETTERS Vol. 358 ( 1 ) page： 1 - 3 1995.1

Persistent oxidative stress in cancer

Toyokuni S., Okamoto K., Yodoi J., Hiai H.

FEBS Letters Vol. 358 ( 1 ) page： 1 - 3 1995.1

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

DNA of cancers such as renal cell carcinoma and mammary invasive ductal carcinoma, is persistently exposed to more oxidative stress than that of adjacent nornal tissue. We suggest that the concept of 'persistent oxidative stress in cancer' may open up a new research area, explaining part of the characteristic tumor biology of cancer such as activated transcription factors and proto-oncogenes, genomic instability, chemotherapy-resistance, invasion and metastasis. © 1995.

DOI： 10.1016/0014-5793(94)01368-B

Scopus

Persistent oxidative stress in cancer

TOYOKUNI S.

FEBS Lett. Vol. 358 ( 1 ) page： 1 - 3 1995.1

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