Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Thiobarbituric acid-reactive substance formation of rat kidney brush border membrane vesicles induced by ferric nitrilotriacetate

Hamazaki S., Okada S., Toyokuni S., Midorikawa O.

Archives of Biochemistry and Biophysics Vol. 274 ( 2 ) page： 348 - 354 1989.11

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

An iron chelate, ferric nitrilotriacetate (Fe3+-NTA), is nephrotoxic and also carcinogenic to the kidney in experimental animals. Iron-promoted lipid peroxidation in the proximal tubules is thought to be responsible for the pathologic process. In the present study, iron-promoted lipid peroxidation, with thiobarbituric acid (TBA) formation as an indication, in the tubular surface was simulated in vitro using rat kidney brush border membrane vesicles and the results were compared with those using linoleate micelles and rat liver microsomal lipid liposomes. Addition of ascorbate, cysteine, or dithiothreitol to the Fe3+-NTA solution resulted in consumption of dissolved oxygen and promoted the lipid peroxidation in the micelles and in the liposomes. In contrast, addition of glutathione to the Fe3+-NTA solution caused only sluggish oxygen consumption and far less peroxidation in these lipid systems. When the brush border membrane vesicles were used for the peroxidation substrate, Fe3+-NTA and glutathione could promote TBA formation at a rate comparable to that elicited by Fe3+-NTA with cysteine or dithiothreitol. Acivicin, a γ-glutamyl transpeptidase inhibitor, suppressed the peroxidation of the brush border membrane vesicles promoted by Fe3+-NTA and glutathione. These results suggest the following mechanism of proximal tubular cell lipid peroxidation promoted by Fe-NTA: Fe3+-NTA filtered through glomeruli is rapidly reduced by cysteine and Fe2+-NTA starts lipid peroxidation at the site, leading to proximal tubular necrosis. Cysteine is amply supplied by the decomposition of glutathione within the lumen by the action of γ-glutamyl transpeptidase and dipeptidase situated at the proximal tubular brush border membrane. © 1989.

DOI： 10.1016/0003-9861(89)90448-7

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INDUCTION OF MESOTHELIOMA BY INTRAPERITONEAL INJECTIONS OF FERRIC SACCHARATE IN MALE WISTAR RATS

OKADA S, HAMAZAKI S, TOYOKUNI S, MIDORIKAWA O

BRITISH JOURNAL OF CANCER Vol. 60 ( 5 ) page： 708 - 711 1989.11

THIOBARBITURIC ACID-REACTIVE SUBSTANCE FORMATION OF RAT-KIDNEY BRUSH-BORDER MEMBRANE-VESICLES INDUCED BY FERRIC NITRILOTRIACETATE Reviewed

S HAMAZAKI, S OKADA, S TOYOKUNI, O MIDORIKAWA

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 274 ( 2 ) page： 348 - 354 1989.11

Induction of mesothelioma by intraperitoneal injections of ferric saccharate in male wistar rats

Okada S., Hamazaki S., Toyokuni S., Midorikawa O.

British Journal of Cancer Vol. 60 ( 5 ) page： 708 - 711 1989.11

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

Iron appears to play a major role in catalysing free radical production, leading to lipid peroxidation and DNA damage. We, therefore, investigated the effect of colloidal iron deposited in the peritoneum. Wistar male rats were given either ferric saccharate, ferric saccharate and nitrilotriacetic acid (NTA), NTA or saline. NTA was shown previously to ‘free’ iron to promote lipid peroxidation and an iron chelate of NTA is known to be carcinogenic to the kidney. Iron at a dose of 5 mg kg-1 day-1, and saline at a dose of 0.5 ml day-1 were injected i.p. for 3 months. NTA at a dose of 83.5 mg kg-1 day1 was give i.p for 5 months. All the rats were killed about a year later for histological examination. In nine of the 19 rats treated with ferric saccharate, mesothelial tumors were induced in the serosa of the tunica vaginalis or the length of the spermatic cord. Among rats treated with ferric saccharate and NTA, seven had localised mesotheliomas in the above locations and six had wide-spread peritoneal mesotheliomas. No mesothelial tumors developed in either NTA treated or saline treated rats. No pleural mesotheliomas were found in any group. These findings add to the evidence that iron is involved in some carcinogenic processes. © The Macmillan Press Ltd., 1989.

DOI： 10.1038/bjc.1989.344

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Induction of mesothelioma by intraperitoneal injections of ferric saccharate in male Wistar rats

OKADA S.

Br J Cancer Vol. 60 ( 5 ) page： 708 - 711 1989.11

OXYGEN REDUCTION AND LIPID-PEROXIDATION BY IRON CHELATES WITH SPECIAL REFERENCE TO FERRIC NITRILOTRIACETATE

HAMAZAKI S, OKADA S, LI JL, TOYOKUNI S, MIDORIKAWA O

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 272 ( 1 ) page： 10 - 17 1989.7

OXYGEN REDUCTION AND LIPID-PEROXIDATION BY IRON CHELATES WITH SPECIAL REFERENCE TO FERRIC NITRILOTRIACETATE Reviewed

S HAMAZAKI, S OKADA, JL LI, S TOYOKUNI, O MIDORIKAWA

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 272 ( 1 ) page： 10 - 17 1989.7

Oxygen reduction and lipid peroxidation by iron chelates with special reference to ferric nitrilotriacetate

Hamazaki S., Okada S., Li J., Toyokuni S., Midorikawa O.

Archives of Biochemistry and Biophysics Vol. 272 ( 1 ) page： 10 - 17 1989.7

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

A certain iron chelate, ferric nitrilotriacetate (Fe3+-NTA) is nephrotoxic and also carcinogenic to the kidney in mice and rats, a distinguishing feature not shared by other iron chelates tested so far. Iron-promoted lipid peroxidation is thought to be responsible for the initial events. We examined its ability to initiate lipid peroxidation in vitro in comparison with that of other ferric chelates. Chelation of Fe2+ by nitrilotriacetate (NTA) enhanced the autoxidation of Fe2+. In the presence of Fe2+-NTA, lipid peroxidation occurred as measured by the formation of conjugated diene in detergent-dispersed linoleate micelles, and by the formation of thiobarbituric acid-reactive substances in the liposomes of rat liver microsomal lipids. Addition of ascorbic acid to Fe3+-NTA solution promoted dose-dependent consumption of dissolved oxygen, which indicates temporary reduction of iron. On reduction, Fe3+-NTA initiated lipid peroxidation both in the linoleate micelles and in the liposomes. Fe3+-NTA also initiated NADPH-dependent lipid peroxidation in rat liver microsomes. Although other chelators used (deferoxamine, EDTA, diethylenetriaminepentaacetic acid, ADP) enhanced autoxidation, reduction by ascorbic acid, or in vitro lipid peroxidation of linoleate micelles or liposomal lipids, NTA was the sole chelator that enhanced all the reactions. © 1989.

DOI： 10.1016/0003-9861(89)90188-4

Scopus

CIRRHOSIS OF THE LIVER INDUCED BY CUPRIC NITRILOTRIACETATE IN WISTAR RATS - AN EXPERIMENTAL-MODEL OF COPPER TOXICOSIS

TOYOKUNI S, OKADA S, HAMAZAKI S, FUJIOKA M, LI JL, MIDORIKAWA O

AMERICAN JOURNAL OF PATHOLOGY Vol. 134 ( 6 ) page： 1263 - 1274 1989.6

CIRRHOSIS OF THE LIVER INDUCED BY CUPRIC NITRILOTRIACETATE IN WISTAR RATS - AN EXPERIMENTAL-MODEL OF COPPER TOXICOSIS Reviewed

S TOYOKUNI, S OKADA, S HAMAZAKI, M FUJIOKA, JL LI, O MIDORIKAWA

AMERICAN JOURNAL OF PATHOLOGY Vol. 134 ( 6 ) page： 1263 - 1274 1989.6

Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats. An experimental model of copper toxicosis.

Toyokuni S, Okada S, Hamazaki S, Fujioka M, Li JL, Midorikawa O

The American journal of pathology Vol. 134 ( 6 ) page： 1263 - 74 1989.6

Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats: an experimental model of copper toxicosis. Reviewed

Toyokuni S, Okada S, Hamazaki S, Fujioka M, Li J-L and Midorikawa O.

Am. J. Pathol. Vol. 134 page： 1263-1274 1989

Oxygen reduction and lipid peroxidation by iron chelates with special reference to ferric nitrilotriacetate. Reviewed

Hamazaki S, Okada S, Li J-L, Toyokuni S and Midorikawa O.

Arch. Biochem. Biophys. Vol. 272 page： 10-17 1989

Nasal T-cell lymphoma associated with double gammopathy; A case report. International journal Open Access

Omori Koichi, Kojima Hisayoshi, Nonomura Mitsuharu, Kanaji Myojo, Toyokuno Shinya

Practica Oto-Rhino-Laryngologica Vol. 82 ( 12 ) page： 1739 - 1744 1989

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Society of Practical Otolaryngology

Nasal T-cell lymphoma associated with double gammopathy (IgG and IgA) was found in a 78-year-old man with a necrotic tumor in his right nasal cavity. He was treated with radiotherapy and CVP chemotherapy but the lymphoma relapsed in his left nasal cavity 1 year later. He was treated again with the same therapy and is now alive and tumor-free.<br>Two serum M-components (IgG and IgA) were detected through his clinical course. To our knowledge, this is the first report of T-cell lymphoma associated with double gammopathy. The significance of M-components in T-cell lymphocytic proliferation remains unclear, but it may be that the M-components appear because of the inappropriate regulation of the T-B immune-response system in the presence of T-cell lymphoma.<br>Histology in this case is also noteworthy. The first nasal tumor showed granulation and necrotic tissue with plasma cell infiltration; it was diagnosed as non-Hodgkin diffuse lymphoma, mixed type, by surface marker analysis. This indicates that immunohistochemical study is indispensable for the diagnosis of nasal non-healing granuloma with necrosis.

DOI： 10.5631/jibirin.82.1739

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Renal changes induced by chronic oral administration of potassium bromate of ferric nitrilotriacetate in Wistar rats Reviewed International journal

K. Nakano, S. Okada, S. Toyokuni, O. Midorikawa

Japanese Archives of Internal Medicine Vol. 36 ( 2 ) page： 41 - 47 1989

Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats. An experimental model of copper toxicosis Reviewed International journal

Toyokuni S., Okada S., Hamazaki S., Fujioka M., Li J.L., Midorikawa O.

American Journal of Pathology Vol. 134 ( 6 ) page： 1263 - 1274 1989

Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Pathology

Rats intraperitoneally injected with a daily dose of cupric nitrilotriacetate (Cu-NTA), which contained 4 to 7 mg of copper/kg body weight, showed submassive liver necrosis, hemolytic anemia, and acute renal tubular necrosis at the beginning of the experiment and intermittently after 4 weeks of injections. All rats that survived over 8 weeks exhibited liver fibrosis with portal-portal, portal-central, and central-central bridging. In all rats that survived over 16 weeks, micronodular cirrhosis of the liver or extensive liver fibrosis was observed. The copper content of the cirrhotic/fibrotic liver was above 250 μg/g dry weight. Electron-microscopic x-ray analysis at day 93 revealed that copper stored in secondary lysosomes was always accompanied by a proportional amount of sulfur (correlation coefficient, 0.98; P < 0.005). An experimental model of copper toxicosis in terms of copper-induced cirrhosis of the liver was established with exogenous copper chelated by nitrilotriacetate.

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