研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis. 国際誌

Kawamura, K, Kageyama, F, Kobayashi, Y, Kawasaki, T, Toyokuni, S, Uchida, K

HEPATOLOGY 30 巻 ( 4 ) 頁： 543A - 543A 1999年10月

P-58 Ontogenesis of Anti-Oxidative Enzymes and Effects of Oxygen Stress on Developing Mouse Embryos.

KOBAYASHI M., NAKAMURA H., YODOI J., TOYOKUNI S., SHIOTA K.

Congenital anomalies 39 巻 ( 3 ) 頁： 175 1999年9月

P-58 Ontogenesis of Anti-Oxidative Enzymes and Effects of Oxygen Stress on Developing Mouse Embryos.

KOBAYASHI M, NAKAMURA H, YODOI J, TOYOKUNI S, SHIOTA K

Congenital anomalies 39 巻 ( 3 ) 1999年9月

Iron chelators modulate the production of DNA strand breaks and 8-hydroxy-2'-deoxyguanosine

Toyokuni S., Sagripanti J.

Free Radical Research 31 巻 ( 2 ) 頁： 123 - 128 1999年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Research

The interaction of chelators and reducing agents is of particular importance in understanding iron-associated pathology since catalytic iron undergoes cyclic reduction and oxidation in vivo. Therefore, we treated plasmid DNA with free or chelated Fe(III) in the presence of biological reductants, and simultaneously measured the number of single strand breaks (SSBs) and oxidative base modification (8-hydroxy-2'-deoxyguanosine; 8-OHdG) by quantitative gel electrophoresis and HPLC with electrochemical detection, respectively. Production of SSBs and 8-OHdG was linearly correlated suggesting that these true different lesions share a common chemical mechanism. The levels of both lesions were enhanced when Fe(III) was chelated to citrate or nitrilotriacetic acid. Reducing agents showed different potency in inducing DNA damage catalyzed by chelated iron (L-ascorbate > L-cysteine > H2O2). Chelation increased SSB formation by ~ 8-fold and 8-OHdG production by ~ 4-fold. The ratio of SSB/8-OHdG catalyzed by chelated iron, which is twice as high as by unchelated iron, indicates that chelation affects iron-catalyzed oxidative DNA damage in a specific way favoring strand breakage over base modification. Since iron is mostly chelated in biological systems, the production of genomic and mitochondrial DNA damage, particularly strand breaks, in diseases involving iron overload is likely to be higher than previously predicted from studies using unchelated iron.

DOI： 10.1080/10715769900301631

Scopus

Localization of hydroxynonenal protein adducts in normal human kidney and selected human kidney cancers

Oberley TD, Toyokuni S, Szweda LI

FREE RADICAL BIOLOGY AND MEDICINE 27 巻 ( 5-6 ) 頁： 695 - 703 1999年9月

Localization of hydroxynonenal protein adducts in normal human kidney and selected human kidney cancers 査読有り

TD Oberley, S Toyokuni, LI Szweda

FREE RADICAL BIOLOGY AND MEDICINE 27 巻 ( 5-6 ) 頁： 695 - 703 1999年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Both polyclonal and monoclonal antibodies to 4-hydroxy-2-nonenal (HNE) protein adducts were used to identify lipid peroxidation products in normal human kidney and in selected human kidney cancers using immunoperoxidase techniques at the light microscopic level and immunogold techniques at the ultrastructural level. HNE protein adducts were detected in most cell types in normal kidney, although in highly variable amounts. All six morphologic types of renal tumors examined showed some staining with antibodies to HNE protein adducts, although the intensity of staining Varied considerably depending on tumor type. Renal oncocytoma and the granular cell variant of renal adenocarcinoma both showed greater cytoplasmic staining for HNE protein adducts than the other tumors examined; these tumors both contain high numbers of mitochondria and suggest that mitochondria are a major source of lipid peroxidation products. To test this possibility, immunogold ultrastructural analysis was performed. HNE protein adducts were identified in nuclei and mitochondria in both normal proximal tubule and three types of renal carcinoma examined; these results localize oxidative damage at the subcellular level in both benign and malignant epithelium to nuclei and mitochondria. In conclusion, HNE protein adducts occur in kidneys in both normal and tumor cells, although immunomorphologic analyses suggest less HNE protein adducts in tumor cells. (C) 1999 Elsevier Science Inc.

DOI： 10.1016/S0891-5849(99)00117-3

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Association between M/L55-polymorphism of paraoxonase enzyme and oxidative DNA damage in patients with type 2 diabetes mellitus and in control subjects

Malin R., Rantalaiho V., Huang X.H., Wirta O., Pasternack A., Leinonen J.S., Alho H., Jokela H., Koivula T., Tanaka T., Okada K., Ochi H., Toyokuni S., Lehtimäki T.

Human Genetics 105 巻 ( 1-2 ) 頁： 179 - 180 1999年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Human Genetics

The paraoxonase enzyme (PON) gene polymorphism causes a change of methionine (M-allele) to leucine (L-allele). PON may reduce low density lipoprotein oxidation and prevent atherosclerosis. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a sensitive index of oxidative DNA damage. We have studied the association between the PON genotypes and the urinary excretion of 8-OHdG. The study population consisted of 93 Finnish type 2 diabetes patients and 106 non-diabetic control subjects. The 24-h excretion of 8-OHdG was significantly higher in diabetic patients than in control subjects (P < 0.001). In control subjects, the ratio of the 8-OHdG/glomerular filtration rate increased in order of genotype from MM to ML to LL (P < 0.0412). These results suggest that lipid peroxidation may have an effect on DNA oxidation.

DOI： 10.1007/s004399900074

Scopus

4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress - Identification of proteasomes as target molecules 査読有り国際誌

Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K

JOURNAL OF BIOLOGICAL CHEMISTRY 274 巻 ( 34 ) 頁： 23787 - 23793 1999年8月

4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules Open Access

Okada K., Wangpoengtrakul C., Osawa T., Toyokuni S., Tanaka K., Uchida K.

Journal of Biological Chemistry 274 巻 ( 34 ) 頁： 23787 - 23793 1999年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

Oxidative stress is associated with important pathophysiological events in a variety of diseases. It has been postulated that free radicals and lipid peroxidation products generated during the process may be responsible for these effects because of their ability to damage cellular components such as membranes, proteins, and DNA. In the present study, we provide evidence that oxidative stress causes a transient impairment of intracellular proteolysis via covalent binding of 4-hydroxy-2-nonenal (HNE), a major end product of lipid peroxidation, to proteasomes. A single intraperitoneal treatment with the renal carcinogen, ferric nitrilotriacetate, caused oxidative stress, as monitored by accumulation of lipid peroxidation products and 8-hydroxy-2'- deoxyguanosine, in the kidney of mice. In addition, transient accumulation of HNE-modified proteins in the kidney was also found by competitive enzyme- linked immunosorbent assay and immunohistochemical analyses. This and the observation that the HNE-modified proteins were significantly ubiquitinated suggested a crucial role of proteasomes in the metabolism of HNE-modified proteins. In vitro incubation of the kidney homogenates with HNE indeed resulted in a transient accumulation of HNE-modified proteins, whereas the proteasome inhibitor significantly suppressed the time-dependent elimination of HNE-modified proteins. We found that, among three proteolytic activities (trypsin, chymotrypsin, and peptidylglutamyl peptide hydrolase activities) of proteasomes, both trypsin and peptidylglutamyl peptide hydrolase activities in the kidney were transiently diminished in accordance with the accumulation of HNE-modified proteins during oxidative stress. The loss of proteasome activities was partially ascribed to the direct attachment of HNE to the protein, based on the detection of HNE-proteasome conjugates by an immunoprecipitation technique. These results suggest that HNE may contribute to the enhanced accumulation of oxidatively modified proteins via an impairment of ubiquitin/proteasome-dependent intracellular proteolysis.

DOI： 10.1074/jbc.274.34.23787

Open Access

Scopus

Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

Kondo S, Toyokuni S, Iwasa Y, Tanaka T, Onodera H, Hiai H, Imamura M

FREE RADICAL BIOLOGY AND MEDICINE 27 巻 ( 3-4 ) 頁： 401 - 410 1999年8月

Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

Kondo S., Toyokuni S., Iwasa Y., Tanaka T., Onodera H., Hiai H., Imamura M.

Free Radical Biology and Medicine 27 巻 ( 3-4 ) 頁： 401 - 410 1999年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Biology and Medicine

Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'- deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3- nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.

DOI： 10.1016/S0891-5849(99)00087-8

Scopus

The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2 '-deoxyguanosine in arsenic-related Bowen's disease

Matsui M, Nishigori C, Toyokuni S, Takada J, Akaboshi M, Ishikawa M, Imamura S, Miyachi Y

JOURNAL OF INVESTIGATIVE DERMATOLOGY 113 巻 ( 1 ) 頁： 26 - 31 1999年7月

The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2 '-deoxyguanosine in arsenic-related Bowen's disease

Matsui M, Nishigori C, Toyokuni S, Takada J, Akaboshi M, Ishikawa M, Imamura S, Miyachi Y

JOURNAL OF INVESTIGATIVE DERMATOLOGY 113 巻 ( 1 ) 頁： 26 - 31 1999年7月

High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S

ONCOGENE 18 巻 ( 25 ) 頁： 3793 - 3797 1999年6月

High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Tanaka T., Iwasa Y., Kondo S., Hiai H., Toyokuni S.

Oncogene 18 巻 ( 25 ) 頁： 3793 - 3797 1999年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncogene

Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules, a consequence of Fenton-like reaction, that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In order to find common genetic alterations in this oxystress-induced carcinogengesis model, RCCs were produced in F1 hybrid rats between Wistar and Long-Evans strains and genomes were screened for loss of heterozygosity (LOH) with microsatellite polymorphic markers by PCR. Five consecutive markers on chromosome 5 (D5Mgh5, D5Mit9, D5Mgh6, D5Mit11 and D5Mit6) showed LOH in ≥ 40% of the RCCs. As possible candidate tumor suppressor genes on chromosome 5, p15(INK4B) and p16(INK4A) were investigated for genetic alteration and aberrant methylation by Southern blot, PCR/SSCP/sequencing and methylation-specific PCR. Genetic alteration (homozygous or hemizygous deletion with or without point mutation) or aberrant methylation were found in 30.7 and 53.8% of the RCC cases, respectively, which was proportionally associated with the histological nuclear grade and metastatic activity. Our data suggest that inactivation of p15 and p16 genes could be one of the major pathways responsible for oxystress-induced carcinogenesis.

DOI： 10.1038/sj.onc.1202707

Scopus

High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S

ONCOGENE 18 巻 ( 25 ) 頁： 3793 - 3797 1999年6月

A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method 査読有り国際誌

Satoh K, Yamada S, Koike Y, Igarashi Y, Toyokuni S, Kumano T, Takahata T, Hayakari M, Tsuchida S, Uchida K

ANALYTICAL BIOCHEMISTRY 270 巻 ( 2 ) 頁： 323 - 328 1999年6月

A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method

Satoh K., Yamada S., Koike Y., Igarashi Y., Toyokuni S., Kumano T., Takahata T., Hayakari M., Tsuchida S., Uchida K.

Analytical Biochemistry 270 巻 ( 2 ) 頁： 323 - 328 1999年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Analytical Biochemistry

A simple and rapid enzyme-linked immunosorbent assay (ELISA) method for quantitation of acrolein and 4-hydroxy-2-nonenal (HNE)-modified proteins was developed. Microtiter plate wells were precoated and blocked simultaneously with epitope-bound bovine caseins as matrix proteins, and aldehyde-modified proteins were quantitated by a competition assay with a monoclonal antibody specific for acrolein-modified lysine or HNE-modified histidine epitopes. Minimal reaction times required for the coating/blocking; first monoclonal antibody and the peroxidase-conjugated second antibody binding steps were 3, 3, and 7 min, respectively, the former two steps being found to be or akin to diffusion-rate-limiting reactions. The convenient ELISA should find an application for analyses of the intricate processes involved in oxidative stress and carcinogenic insult. The epitope-attachment methodology may also be advantageous for the quantitation of various other biologically important haptenic molecules.

DOI： 10.1006/abio.1999.4073

Scopus

A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method 査読有り国際誌

Satoh K, Yamada S, Koike Y, Igarashi Y, Toyokuni S, Kumano T, Takahata T, Hayakari M, Tsuchida S, Uchida K

ANALYTICAL BIOCHEMISTRY 270 巻 ( 2 ) 頁： 323 - 328 1999年6月

Intranuclear distribution of 8-hydroxy-2 '-deoxyguanosine: An immunocytochemical study

Toyokuni S, Iwasa Y, Kondo S, Tanaka T, Ochi H, Hiai H

JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY 47 巻 ( 6 ) 頁： 833 - 835 1999年6月

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