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SIGNIFICANCE OF FREE RADICAL-INDUCED DNA AND PROTEIN DAMAGE AND MODIFICATIONS ON CARCINOGENESIS

Research Project

Project/Area Number 07670241
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

TOYOKUNI Shinya  DEPARTMENT OF PATHOLOGY AND BIOLOGY OF DISEASES,GRADUATE SCHOOL OF MEDICINE,KYOTO UNIVERSITY,LECTURER, 医学研究科, 講師 (90252460)

Co-Investigator(Kenkyū-buntansha) HIAI Hiroshi  DEPARTMENT OF PATHOLOGY AND BIOLOGY OF DISEASES,GRADUATE SCHOOL OF MEDICINE,KYOT, 医学研究科, 教授 (10073131)
山田 義博  京都大学, 医学研究科, 助手 (30252464)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1996: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1995: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsFREE RADICAL / OXIDATIVE STRESS / CARCINOGENESIS / IRON / DNA BASE MODIFICATION / LIPID PEROXIDATION / 酸化的DNA損傷 / 8-ヒドロキシグアニン / 鉄ニトリロ三酢酸 / 腎癌 / ras / p53 / 4-ヒドロキシ-2-ノネナ-ル
Research Abstract

It is established that free radicals are involved in a diversity of biological phenomena such as mutation, carcinogenesis, ischemia-reperfusion injury, and irradiation/ultraviolet damage. We have thus far reported that free radicals are deeply involved in the carcinogenic process of ferric nitrilotriacetate (Fe-NTA) -induced rat renal cell carcinoma model. The purpose of this study is 1) to identify rate-limiting genes for Fe-NTA-induced renal carcinogenesis and further explore the presence of mutations and the expression of the identified genes, and 2) to clarify carcinogenic mechanisms by analyzing modified molecules by free radicals.
We used two strategies for identifying the target genes : 1) evaluation of genes associated with free radical metabolism ; 2) the analysis of known oncogene or oncosuppressor gene, ras and p53. We have found the specific induction of glutathione S-transferase pi in the early stage of this carcinogenesis model. We also found no incidence of mutations in H,K,and N-ras genes and a low incidence of p53 mutations in the induced renal cell carcinomas.
Then, we analyzed the products modified by free radical reaction. Main targets for free radicals reactions are lipids, nucleic acids and proteins, and an increasing number of products are reported every year. We suppose, however, limited number of molecules have biological meaning. We have measured using gas chromatography/mass spectrometry the amount of C2-12 saturated and unsaturated aldehydes in the kidney of rats treated with Fe-NTA,and found that 4-hydroxy-2-nonenal (HNE) shows the highest increase. HNE reacts with cysteine, histidine or lysine residues of proteins. We made monoclonal antibodies for HNE-modified proteins, and analyzed renal samples after Fe-NTA treatment by ELISA and immunohistochemistry.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Toyokuni S. Sagripant : J-L, Hitchins VM: "Cytotoxic and mutageuic effccts of ferric uitviltriacetate on L5178Y mouse lympuowa cells." Cancer Lett. 88. 157-162 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S, Miyake N, Hiai H et al.: "The monoclonal autibody specific for the 4-hydroxy-2-norenal histidin addect." FEBS Lett. 359. 189-191 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S, Mori T, Hiai H, Dizdaroglu M: "Treatuent of Wistar rats with a reual carciuogen, ferric nitrilotriacetate, causes DNA-protein cross-liuking between thyeri and tyrosine in their reual chrometin." Lut J Caucer. 62. 309-313 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishiyawa Y, Suwa H, Okamoto K et al.: "Low incidence of point mutatious in H-, K-and N-yas oncogenes and p53 tumer suppressor gene in reual carciuoma and peritoneal mesotheliema of Wistar rats inbuded by ferric uitrilotracetate." Jpn J Cance Res. 86. 1150-1158 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S, Sugripant : J-L: "Association between 8-hydroxy-2'-deoxyguanosive formation and DNA strand breaks medialed by copper and irou." Free Radic Biol Med. 20. 859-864 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S: "Iron-inderced carcins geresis : The rob of redox regulation" Free Radir Biol Med. 20. 553-566 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S.: "Sagripanti J-L and Hitichins VM.Cytotoxic and mutagenic effects of ferric nitrilotriacetate on L5178Y mouse lymphoma cells." Cancer Lett. 88. 157-162 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S,Miyake N,Hiai H,Hagiwara M,Kawakishi S,Osawa T and Uchida K.: "The monoclonal antibody apecific for the 4-hydroxy-2-nonenal histidine adduct." FEBS Lett. 359. 189-191 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S,Mori T,Hiai H and Dizdarolu M.: "Treatment of Wistar rats with arenal carcinogen, ferric nitrilotriacetate, causes DNA-protein cross-linking between thymine and tyrosine in their renal chromatin." Int J Cancer. 62. 309-313 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishiyam Y,Suwa H,Okamoto K,Fukumoto M,Hiai H and Toyokuni S.: "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." Jpn J Cancer Res. 86. 1150-1158 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S and Sagripanti J-L.: "Association between 8-hydroxy-2'-deoxyguanosine formation and DNA strand breaks mediated by copper and iron." Free Radic Biol Med. 20. 859-864 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S.: "Iron-induced carcinogenesis : the role of redox regulation." Free Radic Biol Med. 20. 553-566 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Toyokuni S: "Sagripanti J-L and Hitichins VM.Cytotoxic and mutagenic effects of ferric nitrilotriacetate on L5178Y mouse lymphoma cells." Cancer Lett. 88. 1995 (157-162)

    • Related Report
      1996 Annual Research Report
  • [Publications] Toyokuni S,Miyake N,Hiai H,Hagiwara M,Kawakishi S,Osawa T and Uchida K: "The monoclonal antibody specific for the 4-hydroxy-2-nonenal histidine adduct." FEBS Lett. 359. 1995 (189-191)

    • Related Report
      1996 Annual Research Report
  • [Publications] Toyokuni S,Mori T,Hiai H and Dizdarolu M: "Treatment of Wistar rats with a renal carcinogen,ferric nitrilotriacetate,causes DNA-protein cross-linking between thymine and tyrosine in their renal chromatin." Int J Cancer. 62. 1995 (309-313)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nishiyama Y,Suwa H,Okamoto K,Fukumoto M,Hiai H and Toyokuni S: "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" Jpn J Cancer Res. 86. 1995 (1150-1158)

    • Related Report
      1996 Annual Research Report
  • [Publications] Toyokuni S and Sagripanti J-L: "Association between 8-hydroxy-2′-deoxyguanosine formation and DNA strand breaks mediated by copper and iron" Free Radic Biol Med. 20. 1996 (859-864)

    • Related Report
      1996 Annual Research Report
  • [Publications] Toyokuni S: "Iron-induced carcinogenesis : the role of redox regulation" Free Radic Biol Med. 20. 1996 (553-566)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nishiyama Y et al.: "Low inciderce of point wutations in H-, K- and N-ras oucogenes and p53 tuwor suppressor gene in renal cell carcinowa and peritoneal mesothelioma of Wistar rats induced by ferric uitrilotriacetate" Jpn. J. Cancer Res.86. 1150-1158 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Toyokuni et al.: "Treatment of Wistar rats with a renal carcinogen ; ferric nitrilotriacetate causes DNA-protein cross-linking between thymine and tyrosine in their rcnal chromatin" Int. J. Cancer. 62. 309-313 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Toyokuni et al.: "The wonoclnal antibody specific for the 4-hydroxy-2-nonenal histidine adduct" FEBS Lett. 359. 189-191 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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