Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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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

ACUTE NEPHROTOXICITY OF A CARCINOGENIC IRON CHELATE - SELECTIVE-INHIBITION OF A PROTEOLYTIC CONVERSION OF ALPHA(2U)-GLOBULIN TO THE KIDNEY FATTY-ACID-BINDING PROTEIN Reviewed International journal

UCHIDA K, FUKUDA A, KAWAKISHI S, TOYOKUNI S, HIAI H, IKEDA S, HORIO F

FEBS LETTERS Vol. 357 ( 2 ) page： 165 - 167 1995.1

Acute nephrotoxicity of a carcinogenic iron chelate Selective inhibition of a proteolytic conversion of α<inf>2U</inf>-globulin to the kidney fatty acid-binding protein

Uchida K., Fukuda A., Kawakishi S., Toyokuni S., Hiai H., Ikeda S., Horio F.

FEBS Letters Vol. 357 ( 2 ) page： 165 - 167 1995.1

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

The mechanism of acute nephrotoxicity of an iron chelate in vivo has been investigated. Administration of a renal carcinogen ferric nitrolotriacetate (Fe-NTA) (15 mg Fe/kg body weight, intraperitoneally) led to selective loss of a renal protein with an apparent molecular mass of 17 kDa. Analysis of the 17 kDa protein by NH2-terminal sequence demonstrated its identity over 16 NH2-terminal residues as a kidney fatty acid-binding protein (k-FABP) that is a proteolytically modified form of α2U-globulin, a major urinary protein of adult male rats. An immunochemical study using anti-α2U-globulin polyclonal antibodies confirmed that a single injection of Fe-NTA led to a decrease in k-FABP levels. However, a 19-kDa protein identical to the α2U-globulin progressively appeared in the kidney, suggesting that the proteolytic processing of α2U-globulin in the renal proximal tubules was suppressed by the treatment with Fe-NTA. By monitoring k-FABP and its precursor α2U-globulin, it was determined that repeated exposure to Fe-NTA caused suppression of both proteolytic and endocytotic activity of the kidney. The implications of these data in relation to the nephrotoxicity of Fe-NTA are discussed. © 1995.

DOI： 10.1016/0014-5793(94)01330-4

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4-Hydroxy-2-nonenal-trapping elisa: Direct evidence for the release of a cytotoxic aldehyde from oxidized low density lipoproteins

Uchida K., Osawa T., Hiai H., Toyokuni S.

Biochemical and Biophysical Research Communications Vol. 212 ( 3 ) page： 1068 - 1073 1995

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

Among the aldehydes that originate from the peroxidation of cellular membrane lipids, 4-hydroxy-2-nonenal (HNE) is thought to be largely responsible for cytopathological effects observed during oxidative stress. Taking advantage of the fact that HNE is very reactive with proteins and forms stable Michael addition-type adducts, a novel immunochemical procedure for quantifying “free” HNE has been developed. The method designated as “HNE-trapping ELISA” is based on the detection of HNE trapped by a protein that has been coated in the immunoplate. The HNE-derived epitopes generated in the coating protein are then detected by the ELISA using a monoclonal antibody (mAbHNEJ-2) specific to the haptenic groups of the HNE-protein conjugates. Using this method, we determined that a considerable amount of HNE was released from human plasma low density lipoproteins (LDL) treated with copper ions or endothelial cells. © 1995 by Academic Press, Inc.

DOI： 10.1006/bbrc.1995.2078

Scopus

MICHAEL ADDITION-TYPE 4-HYDROXY-2-NONENAL ADDUCTS IN MODIFIED LOW-DENSITY LIPOPROTEINS - MARKERS FOR ATHEROSCLEROSIS Reviewed International journal

UCHIDA K, TOYOKUNI S, NISHIKAWA K, KAWAKISHI S, ODA H, HIAI H, STADTMAN ER

BIOCHEMISTRY Vol. 33 ( 41 ) page： 12487 - 12494 1994.10

Michael addition type 4-hydroxy-2-nonenal adducts in modified low density lipoproteins : markers for atherosclerosi Reviewed International journal

UCHIDA K.

Biochemistry. Vol. 33 ( 41 ) page： 12487 - 12494 1994.10

Michael Addition-Type 4-Hydroxy-2-nonenal Adducts in Modified Low-Density Lipoproteins: Markers for Atherosclerosis

Uchida K., Toyokuni S., Nishikawa K., Kawakishi S., Oda H., Hiai H., Stadtman E.

Biochemistry Vol. 33 ( 41 ) page： 12487 - 12494 1994.10

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

It has been proposed that plasma low-density lipoprotein (Lall-trans-bRDL) undergoes oxidative modification before it can give rise to foam cells in atherosclerosis. Oxidation of LDL generates a variety of reactive aldehyde products including 4-hydroxy-2-nonenal (HNE), which may covalently attach to the LDL apolipoproteins. We here present direct evidence that HNE derivatization of LDL forms Michael additiontype adducts of HNE with histidine and lysine residues of apolipoprotein B-100 (apo B) and also demonstrate the utility of an antibody specific to the HNE adducts generated in the LDL treated with HNE or oxidatively modified by Cu2+ or cultured endothelial cells. HNE adducts present in the LDL that had been treated with HNE were attested to be Michael addition-type adducts on the basis of the fact that incubation of LDL with 1 mM HNE (2 h, 37 °C) resulted primarily in the formation of Michael addition-type HNE-histidine (39.9 mol/mol of LDL) and HNE-lysine (19.3 mol/mol of LDL) adducts. An enzyme-linked immunosorbent assay (ELISA) and an SDS-polyacrylamide gel electrophoresis (SDS-PAGE)/immunoblot analysis of HNE-modified LDL demonstrated that these HNE adducts were detectable with the HNE-specific antibody affinity-purified with the Michael adduct (HNE-histidine) as a ligand. The following lines of evidence indicated the presence of Michael addition-type HNE adducts in the oxidatively modified LDL in vitro: (i) Amino acid analysis of LDL that had been treated with Cu2+ (24 h, 37 °C) demonstrated the presence of a Michael addition-type HNE-histidine adduct (7-9 mol/mol of LDL). (ii) Competitive ELISA demonstrated the inhibition of antibody binding to HNE-modified LDL by the addition of Cu2+- oxidized LDL. (iii) SDS-PAGE/immunoblot analysis of the Cu2+-oxidized LDL demonstrated the appearance of HNE adducts, which were abolished by the addition of a HNE-modified histidyl peptide. Furthermore, HNE adducts were detected in the LDL that had been treated with cultured bovine aortic endothelial cells (24 h, 37 °C). Taken together, this evidence suggests that the Michael addition-type HNE adducts may be reliable markers for atherosclerosis. © 1994, American Chemical Society. All rights reserved.

DOI： 10.1021/bi00207a016

Scopus

FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE AND 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN HUMAN RENAL-CELL CARCINOMA Reviewed International journal

OKAMOTO K, TOYOKUNI S, UCHIDA K, OGAWA O, TAKENEWA J, KAKEHI Y, KINOSHITA H, HATTORINAKAKUKI Y, HIAI H, YOSHIDA O

INTERNATIONAL JOURNAL OF CANCER Vol. 58 ( 6 ) page： 825 - 829 1994.9

Formation of 8‐hydroxy‐2′‐deoxyguanosine and 4‐hydroxy‐2‐nonenal‐modified proteins in human renal‐cell carcinoma

Okamoto K., Toyokuni S., Uchida K., Ogawa O., Takenewa J., Kakehi Y., Kinoshita H., Hattori‐Nakakuki Y., Hiai H., Yoshida O.

International Journal of Cancer Vol. 58 ( 6 ) page： 825 - 829 1994.9

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

To study the possible involvement of reactive oxygen species (ROS) in the tumor biology of human renal‐cell carcinoma (RCC), we analvzed 35 cases of RCC for 2 parameters of oxidative damage: 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), a mutation‐prone DNA‐ base ‐modified product, was measured by means of high‐performance liquid chromatography (HPLC) with an electrochemical (EC) detector, and 4‐hydroxy‐2‐nonenal (HNE)‐modified proteins were measured with a poly‐clonal antibody against HNE‐modified proteins. A 54% higher content of 8‐OHdG was found in RCC than in the corresponding non‐tumorous kidney, suggesting that the DNA of RCC is more exposed to ROS than is the DNA of non‐tumorous kidneys. Immunohistochemistry for HNE‐modified proteins showed a distinct staining pattern of fine to coarse granularity in the cytoplasm of RCC (n = 15), implying that lipid peroxidation products are located in cytoplasmic organelles. These results suggest that RCC constitutionally elaborates more ROS than is produced by the non‐tumorous parts of kidneys. No correlation was found between clinical stage, histology, age or sex and the 2 parameters examined. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910580613

Scopus

FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE AND 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN HUMAN RENAL-CELL CARCINOMA Reviewed International journal

OKAMOTO K, TOYOKUNI S, UCHIDA K, OGAWA O, TAKENEWA J, KAKEHI Y, KINOSHITA H, HATTORINAKAKUKI Y, HIAI H, YOSHIDA O

INTERNATIONAL JOURNAL OF CANCER Vol. 58 ( 6 ) page： 825 - 829 1994.9

FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE IN EPIDERMIS OF HAIRLESS MICE EXPOSED TO NEAR-UV

HATTORINAKAKUKI Y, NISHIGORI C, OKAMOTO K, IMAMURA S, HIAI H, TOYOKUNI S

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 201 ( 3 ) page： 1132 - 1139 1994.6

Formation of 8-Hydroxy-2′-Deoxyguanosine in epidermis of hairless mice exposed to near-UV

Hattori-Nakakuki Y., Nishigori C., Okamoto K., Imamura S., Hiai H., Toyokuni S.

Biochemical and Biophysical Research Communications Vol. 201 ( 3 ) page： 1132 - 1139 1994.6

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

Six-week-old male albino hairless mice (Hos: Hr-1) were exposed to a near-ultraviolet (UV) fluorescent sun lamp (33.5 kJ/m2/hr; wave length > 270 nm with a peak at 312.5 nm) to investigate the induction of oxidative DNA damage in epidermal cells. Significantly higher levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) were detected in a dose-dependent manner in epidermis of mice exposed to near-UV than in those of control animals. The ratio of 8-OHdG in near-UV-exposed/unexposed control was 2.08 ± 0.19 after 168 kJ/m2 exposure, P < 0.01; 3.49 ± 0.36 after 335 kJ/m2 exposure, P < 0.01 (means ± SE). The levels of 8-OHdG decreased with time after near-UV exposure, suggesting the presence of removal and/or repair mechanisms. This is the first report that oxidative DNA base modification is induced in vivo in epidermal cells by near-UV exposure. Oxidative DNA base modification may be one of the causes of sunlight-induced skin carcinogenesis. © 1994 Academic Press, Inc.

DOI： 10.1006/bbrc.1994.1823

Scopus

FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE IN EPIDERMIS OF HAIRLESS MICE EXPOSED TO NEAR-UV

HATTORINAKAKUKI Y, NISHIGORI C, OKAMOTO K, IMAMURA S, HIAI H, TOYOKUNI S

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 201 ( 3 ) page： 1132 - 1139 1994.6

INCREASED 8-HYDROXYDEOXYGUANOSINE IN KIDNEY AND LIVER OF RATS CONTINUOUSLY EXPOSED TO COPPER

TOYOKUNI S, SAGRIPANTI JL

TOXICOLOGY AND APPLIED PHARMACOLOGY Vol. 126 ( 1 ) page： 91 - 97 1994.5

Increased 8-hydroxydeoxyguanosine in kidney and liver of rats continuously exposed to copper

Toyokuni S., Sagripanti J.

Toxicology and Applied Pharmacology Vol. 126 ( 1 ) page： 91 - 97 1994.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Toxicology and Applied Pharmacology

Copper is a ubiquitous metal in the environment, it is a component of dental casting gold alloys and dental amalgams, and it is a main component in some intrauterine contraceptive devices (IUDs). Since copper materials implanted in the human body corrode and release ions into the surrounding tissue, the potential toxicity caused by contact of this metal with bodily fluids needs to be evaluated. We implanted male Wistar rats with osmotic mini pumps that continuously administered saline, CuCl2, or a copper chelate, cupric nitrilotriacetate (Cu-NTA), at a rate of 4 mg copper/kg body wt/day. This experimental design maintained serum copper concentrations at a level 30-70% (CuCl2) or 100-120% (Cu-NTA) higher than in untreated controls. At different times postimplantation, we measured the levels of 8-hydroxydeoxyguanosine (8-OHdG) in DNA of kidney, liver, and tissue surrounding the pump implant, since production of 8-OHdG has been associated with mutagenesis and carcinogenesis. Hepatic and renal levels of 8-OHdG in CuCl2- or Cu-NTA-treated animals were significantly higher than in control animals. In contrast, histopathologic changes in kidneys and livers of rats exposed to CuCl2 and Cu-NTA were limited to mild changes involving hepatic focal necrosis and slightly increased mitotic activity in the renal proximal tubules. These observations suggest that levels of 8-OHdG could be an early marker of copper toxicity. It is unlikely that the high levels of copper at which we observed DNA modification will be encountered after occupational or environmental exposure. A different situation could be found around medical devices that include copper, particularly IUDs, where the amount of copper administered in our experiments could be released in the uterus of women after a few months of continued IUD use. © 1994 Academic Press, Inc.

DOI： 10.1006/taap.1994.1094

Scopus

INCREASED 8-HYDROXYDEOXYGUANOSINE IN KIDNEY AND LIVER OF RATS CONTINUOUSLY EXPOSED TO COPPER

TOYOKUNI S, SAGRIPANTI JL

TOXICOLOGY AND APPLIED PHARMACOLOGY Vol. 126 ( 1 ) page： 91 - 97 1994.5

DNA-BASE MODIFICATIONS IN RENAL CHROMATIN OF WISTAR RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE

TOYOKUNI S, MORI T, DIZDAROGLU M

INTERNATIONAL JOURNAL OF CANCER Vol. 57 ( 1 ) page： 123 - 128 1994.4

DNA base modification in renal chromatin of wister rats trea, ed with a renal carcinogen, ferric nitrilotriacetate

TOYOKUNI S.

Int. J. Cancer Vol. 57 ( 1 ) page： 123 - 128 1994.4

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