2000 Fiscal Year Annual Research Report

特異的代謝制御分子の設計による酸素毒性と循環病態の制御

Research Project

Project/Area Number	11557014
Research Institution	Osaka City University Medical School
Principal Investigator	井上正康大阪市立大学, 医学部, 教授 (80040278)
Co-Investigator(Kenkyū-buntansha)	西川学日本学術振興会, 特別研究員佐藤英介大阪市立大学, 医学部, 助手 (60211942)
Keywords	活性酸素 / 一酸化窒素 / 循環制御 / エネルギー制御 / ミトコンドリア / 変態反応 / アポトーシス / スーパーシステム
Research Abstract	各種疾患にスーパーオキシドやNOの関与が示唆されているが、その分子論的実体は不明である。申請者らは、部位指向性SODを開発し、生体局所でスーパーオキシドの生理機能と病理作用を特異的に制御するシステムを確立してきた。、個体レベルで組織や細胞でスーパーオキシドやNOを特異的に制御(産生と消去)する分子群を開発し、活性酸素・NO代謝系の全容を把握すると同時に、各種病態の予防治療法の開発を目指してきた。本年度の研究では: 1)スーパーオキシド、NO、及び酸素の相互作用が血液循環、エネルギー合成、及び感染防御機能を統合制御するスーパーシステムを構築していることが判明した。 2)本システムはMannose受容体細胞を介して全身の血圧管理にも不可欠であり、その機能不全はショック死を誘起することが判明した。また、本システムの制御により、既存の循環制御剤に抵抗性のショック病態を制御できる可能性が示唆された。 3)本システムは、ミトコンドリアの電子伝達系、内膜電位、チトクロムc膜間分布を制御し、腎、腸脳、筋肉組織などの細胞の生死を決定していることが判明した。 4)本システムは、両棲類の変態などにも利用されており、種を越えて機能している。 5)ほ乳類や両棲類におけるミトコンドリア依存性の細胞死がカルニチンで特異的に抑制されることが判明した。 6)カルニチンの本作用は、腎や消化管における制ガン剤副作用軽減法として極めて有用であり、担癌動物のQOLを著明に改善することが判明した。

Research Products
(14 results)

All Other

All Publications (14 results)

[Publications] C.Sakata,H.Tanaka,S.Takemura,K.Hirohashi,Y.Minamiyama,A.Nakamura,M.Inoue,H.Kinoshita: "Post-ischemic intraportal adenosine administration protects against reperfusion injury of canine liver."J.Hepatobiliary Pancreat Surg. 7・1. 78-85 (2000)
[Publications] M.Kashiba,M.Inoue: "Nitric oxide-independent effects of nitric oxide donors on energy metabolism in erythrocytes."Biochemical Pharmacology. 59・. 557-561 (2000)
[Publications] Y.Takada,E.Sato,T.Nakajima,M.Hosono,M.Tsumura,M.Inoue,R.Yamada: "Granulocyte-colony stimulating factor enhances anti-tumour effect of hyperthermia."Int.J.Hyperthermia. 16・. 275-286 (2000)
[Publications] K.Suzumura,E.Kasahara,Y.Ohnishi.K.C.Chien.M.Inoue: "Fluvastatin normalizes the decreased turnovers of glutathione and ascorbic acid in Watanabe heritable hyperlipidemic rabbits."Clin.Exp.Pharmacol.Physiol.. 27・. 709-714 (2000)
[Publications] K.Suzumura,E.Kasahara,Yi Wang,K.C.Chien,M.Inoue: "Decreased turnovers of glutathione and ascorbic acid in Watanabe heritable hyperlipidemic rabbits"J. Nutr. Sci. Vitaminol.. 46・. 205-209 (2000)
[Publications] A.Nakamura,A.M.Park,K.Nagata,E.Sato,M.Kashiba,T.Tamura,M.Inoue: "Oxidative cellular damage associated with transformation of helicobacter pylori from a bacillary to a coccoid form."Free Radical Biology Medicine. 28・. 1611-1618 (2000)
[Publications] M.Tsuchiya,H.Tokai,Y.Takehara,Y.Haraguchi,A.Asada,K.Utsumi,M.Inoue: "Interrlation betwwen oxygen tension and nitric oxide in the respiratory system."Am J Respir Crit Care Med. 162・. 1257-1261 (2000)
[Publications] M.Kashiba,J.Oka,R.Ichikawa,A.Kageyama,T.Inayama,H.Kageyama,T.Ishikawa,M.Nishikimi,M.Inoue,S.Inoue: "Impaired reductive regeneration of ascorbic acid in the Goto-Kakizaki diabetic rat."Biochem.J.. 351・. 313-318 (2000)
[Publications] M.Tsuchiya,A.Asada,K.Maeda,Y.Ueda,E.Sato,M.Shindo,M.Inoue: "Propofol versus midazolam regarading their antioxidant activities."American Journal of Respiratory and Critical Care Medicine. 163・. 1-6 (2001)
[Publications] Tomita,M.,Sato,EF.,Nishikawa,M.,Yamano,Y.,Imoue,M.: "Nitric oxide regulates mitochondrial respiration and fanctions of articular chondrocytes"Arthritis & Rheumatism. 44・. 96-104 (2001)
[Publications] Takemura,S.,Minamiyama Y.,Inoue,M.,Kubo,S.,Hirohashi,K.,Kinoshita,H.: "Nitric oxide synthase inhibitor increases hepatic injury with formation of oxidative DNA damage and microcirculatory disturbance in endotoxemic rats"Hepato-Gastroenterology. 47・. 1364-1370 (2000)
[Publications] Nishikawa,M.,Nagatomi,H.,Bao-Jun Chang,Sato,E.F,.Inoue,M.: "Targeting superoxide dismutase to renal proximal tuble cells inhibits mitochondrial injury and renal dysfunction induced by cisplatin"Arch.Biochem. & Biophys.. 386・2(in press). (2001)
[Publications] Nishikawa,M.,Nishiguchi,S.,Tamori,A.,Koh,N.,Takeda,T.,Shiomi,S.,Kubo,S.,Hirohashi,K.,Kinoshita,H.,Sato.E.F.,Inoue,M.: "Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma"Cancer Res. (in press). (2001)
[Publications] Nishikimi,A.,Kira,Y.,Kasahara,E.,Sato,EF.,Kanno,T.,Utsumi,K.,Inoue,: "Tributyltin interacts with thiol groups in adenine nucleotide translocator therby inducing cytochrome c release"Biochem J. (in press). (2001)

2000 Fiscal Year Annual Research Report

特異的代謝制御分子の設計による酸素毒性と循環病態の制御

Principal Investigator

井上 正康 大阪市立大学, 医学部, 教授 (80040278)

Research Products

[Publications] C.Sakata,H.Tanaka,S.Takemura,K.Hirohashi,Y.Minamiyama,A.Nakamura,M.Inoue,H.Kinoshita: "Post-ischemic intraportal adenosine administration protects against reperfusion injury of canine liver."J.Hepatobiliary Pancreat Surg. 7・1. 78-85 (2000)

[Publications] M.Kashiba,M.Inoue: "Nitric oxide-independent effects of nitric oxide donors on energy metabolism in erythrocytes."Biochemical Pharmacology. 59・. 557-561 (2000)

[Publications] Y.Takada,E.Sato,T.Nakajima,M.Hosono,M.Tsumura,M.Inoue,R.Yamada: "Granulocyte-colony stimulating factor enhances anti-tumour effect of hyperthermia."Int.J.Hyperthermia. 16・. 275-286 (2000)

[Publications] K.Suzumura,E.Kasahara,Y.Ohnishi.K.C.Chien.M.Inoue: "Fluvastatin normalizes the decreased turnovers of glutathione and ascorbic acid in Watanabe heritable hyperlipidemic rabbits."Clin.Exp.Pharmacol.Physiol.. 27・. 709-714 (2000)

[Publications] K.Suzumura,E.Kasahara,Yi Wang,K.C.Chien,M.Inoue: "Decreased turnovers of glutathione and ascorbic acid in Watanabe heritable hyperlipidemic rabbits"J. Nutr. Sci. Vitaminol.. 46・. 205-209 (2000)

[Publications] A.Nakamura,A.M.Park,K.Nagata,E.Sato,M.Kashiba,T.Tamura,M.Inoue: "Oxidative cellular damage associated with transformation of helicobacter pylori from a bacillary to a coccoid form."Free Radical Biology Medicine. 28・. 1611-1618 (2000)

[Publications] M.Tsuchiya,H.Tokai,Y.Takehara,Y.Haraguchi,A.Asada,K.Utsumi,M.Inoue: "Interrlation betwwen oxygen tension and nitric oxide in the respiratory system."Am J Respir Crit Care Med. 162・. 1257-1261 (2000)

[Publications] M.Kashiba,J.Oka,R.Ichikawa,A.Kageyama,T.Inayama,H.Kageyama,T.Ishikawa,M.Nishikimi,M.Inoue,S.Inoue: "Impaired reductive regeneration of ascorbic acid in the Goto-Kakizaki diabetic rat."Biochem.J.. 351・. 313-318 (2000)

[Publications] M.Tsuchiya,A.Asada,K.Maeda,Y.Ueda,E.Sato,M.Shindo,M.Inoue: "Propofol versus midazolam regarading their antioxidant activities."American Journal of Respiratory and Critical Care Medicine. 163・. 1-6 (2001)

[Publications] Tomita,M.,Sato,EF.,Nishikawa,M.,Yamano,Y.,Imoue,M.: "Nitric oxide regulates mitochondrial respiration and fanctions of articular chondrocytes"Arthritis & Rheumatism. 44・. 96-104 (2001)

[Publications] Takemura,S.,Minamiyama Y.,Inoue,M.,Kubo,S.,Hirohashi,K.,Kinoshita,H.: "Nitric oxide synthase inhibitor increases hepatic injury with formation of oxidative DNA damage and microcirculatory disturbance in endotoxemic rats"Hepato-Gastroenterology. 47・. 1364-1370 (2000)

[Publications] Nishikawa,M.,Nagatomi,H.,Bao-Jun Chang,Sato,E.F,.Inoue,M.: "Targeting superoxide dismutase to renal proximal tuble cells inhibits mitochondrial injury and renal dysfunction induced by cisplatin"Arch.Biochem. & Biophys.. 386・2(in press). (2001)

[Publications] Nishikawa,M.,Nishiguchi,S.,Tamori,A.,Koh,N.,Takeda,T.,Shiomi,S.,Kubo,S.,Hirohashi,K.,Kinoshita,H.,Sato.E.F.,Inoue,M.: "Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma"Cancer Res. (in press). (2001)

[Publications] Nishikimi,A.,Kira,Y.,Kasahara,E.,Sato,EF.,Kanno,T.,Utsumi,K.,Inoue,: "Tributyltin interacts with thiol groups in adenine nucleotide translocator therby inducing cytochrome c release"Biochem J. (in press). (2001)

井上正康大阪市立大学, 医学部, 教授 (80040278)