研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE AND 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN HUMAN RENAL-CELL CARCINOMA 査読有り国際誌

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

INTERNATIONAL JOURNAL OF CANCER 58 巻 ( 6 ) 頁： 825 - 829 1994年9月

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 58 巻 ( 6 ) 頁： 825 - 829 1994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：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 査読有り国際誌

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

INTERNATIONAL JOURNAL OF CANCER 58 巻 ( 6 ) 頁： 825 - 829 1994年9月

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 201 巻 ( 3 ) 頁： 1132 - 1139 1994年6月

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 201 巻 ( 3 ) 頁： 1132 - 1139 1994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：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 201 巻 ( 3 ) 頁： 1132 - 1139 1994年6月

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

TOYOKUNI S, SAGRIPANTI JL

TOXICOLOGY AND APPLIED PHARMACOLOGY 126 巻 ( 1 ) 頁： 91 - 97 1994年5月

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

Toyokuni S., Sagripanti J.

Toxicology and Applied Pharmacology 126 巻 ( 1 ) 頁： 91 - 97 1994年5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：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 126 巻 ( 1 ) 頁： 91 - 97 1994年5月

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 57 巻 ( 1 ) 頁： 123 - 128 1994年4月

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 57 巻 ( 1 ) 頁： 123 - 128 1994年4月

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 57 巻 ( 1 ) 頁： 123 - 128 1994年4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：International Journal of Cancer

Ferric nitrilotriacetate (Fe‐NTA) causes renal proximal tubular necrosis, a consequence of iron ion‐mediated free‐radical‐associated damage, that finally leads to a high incidence of renal ad en oca re in dm a in male rats and mice. We have investigated the levels of typical hydroxyl radical‐induced DNA base modifications in renal chromatin of male Wistar rats treated with a single or repeated administrations of Fe‐NTA. Five pyrimidine‐derived and 5 purine‐derived modified DNA bases were identified and quantified by gas chromatography/mass spectrometry with selected‐ion monitoring. The modified bases were 5‐hydroxy‐5‐methylhydantoin, 5‐(hydroxymethyl)uracil, 5‐hydroxy‐cytosine, thymine glycol, 5,6‐dihydroxyuraril, 4,6‐diamino‐5‐form‐amidopyrimidine, 8‐hydroxyadenine, xanthine, 2‐hydroxyadenine and 8‐hydroxyguanine. The amounts of most of these compounds were significantly increased over control levels in renal chromatin of Fe‐NTA‐treated rats as measured 3 and 24 hr after treatment. Elevated levels of modified bases were accompanied by proximal tubular necrosis. On the 19th day, however, accumulation of modified DNA bases was not observed. Morphologically, scattered karyomegaiic cells were seen in the proximal tubules, but necrosis was rarely found. Some of the identified DNA base lesions are known to be promutagenic., although others have not been investigated. Presence of modified DNA bases concomitant with necrosis and regeneration of the renal proximal tubules may be a critical step in Fe‐NTA‐induced carcinogenesis. © Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910570122

Scopus

FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE 査読有り国際誌

TOYOKUNI S, UCHIDA K, OKAMOTO K, HATTORINAKAKUKI Y, HIAI H, STADTMAN ER

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 91 巻 ( 7 ) 頁： 2616 - 2620 1994年3月

Formation of 4-hydroxy-2-nonenal-modified proteins in the renal proximal tubules of rats treated with a renal carcinogen, ferric nitrilotriacetate

Toyokuni S., Uchida K., Okamoto K., Hattori-Nakakuki Y., Hiai H., Stadtman E.

Proceedings of the National Academy of Sciences of the United States of America 91 巻 ( 7 ) 頁： 2616 - 2620 1994年3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：Proceedings of the National Academy of Sciences of the United States of America

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces proximal tubular necrosis, a consequence of lipid peroxidation, that finally leads to a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation as monitored by formation of thiobarbituric acid-reactive substances and free 4- hydroxy-2-nonenal (HNE) was observed in the kidney homogenates of rats treated with Fe-NTA. Based on the fact that HNE is capable of reacting with cellular proteins, we attempted to detect the localization of HNE-modified proteins in rat kidney tissues with an immunohistochemical procedure. By means of an immunohistochemical technique using polyclonal antibody against the HNE-modified proteins, it was shown that HNE-modified proteins are formed in the target cells of this carcinogenesis model. HNE-modified proteins were detected in the renal proximal tubules 1 hr after i.p. administration of Fe- NTA (15 mg of iron per kg). Intense positivity was found in the cells with degeneration. After 6 hr, the level of HNE-protein conjugates decreased due to the subsequent necrosis. The intensity of the immunochemical reaction with HNE-modified proteins increased in parallel with an increase in the amounts of thiobartituric acid-reactive substances and free HNE that were found. Furthermore, histochemical detection of aldehydes by cold Schiff's reagent demonstrated that location of aldehydes was identical to that of the HNE- modified proteins determined by immunohistochemical procedures. It would thus appear that the production of HNE, a genotoxic and mutagenic aldehyde, and its reaction with proteins may play a role in Fe-NTA-induced renal carcinogenesis.

DOI： 10.1073/pnas.91.7.2616

Scopus

FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE 査読有り国際誌

TOYOKUNI S, UCHIDA K, OKAMOTO K, HATTORINAKAKUKI Y, HIAI H, STADTMAN ER

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 91 巻 ( 7 ) 頁： 2616 - 2620 1994年3月

ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL KH MICE

OKAMOTO K, YAMADA Y, OGAWA MS, TOYOKUNI S, NAKAKUKI Y, IKEDA H, YOSHIDA O, HIAI H

CANCER RESEARCH 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL KH STRAIN MICE

YAMADA Y, MATSUSHIRO H, OGAWA MS, OKAMOTO K, NAKAKUKI Y, TOYOKUNI S, FUKUMOTO M, HIAI H

CANCER RESEARCH 54 巻 ( 2 ) 頁： 403 - 407 1994年1月

ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL KH MICE

OKAMOTO K, YAMADA Y, OGAWA MS, TOYOKUNI S, NAKAKUKI Y, IKEDA H, YOSHIDA O, HIAI H

CANCER RESEARCH 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

Genetic predisposition to pre-B lymphomas in SL/Kh strain mice.

Yamada Y, Matsushiro H, Ogawa MS, Okamoto K, Nakakuki Y, Toyokuni S, Fukumoto M, Hiai H

Cancer research 54 巻 ( 2 ) 頁： 403 - 7 1994年1月

Abnormal bone marrow B-cell differentiation in pre-B lymphoma-prone SL/Kh mice.

Okamoto K, Yamada Y, Ogawa MS, Toyokuni S, Nakakuki Y, Ikeda H, Yoshida O, Hiai H

Cancer research 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

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