1993 Fiscal Year Annual Research Report

部位指向性SODの分子設計と活性酸代謝制御

Research Project

Project/Area Number	05454171
Research Institution	Osaka City University
Principal Investigator	井上正康大阪市立大学, 医学部, 教授 (80040278)
Keywords	superoxide dismutase / free radical / oxygen toxicity / fusion protein / protein engineering / targeting / aging / transplatation
Research Abstract	研究実績概要これまでに、ヒトCu/Zn型SODを用い、アルブミンと可逆的に結合して長時間循環する病巣指向性SM-SOD、長鎖脂肪酸を共有結合した細胞膜脂質親和性AC-SOD、および遺伝子組換えによりヘパラン硫酸に高親和性を示す内皮細胞指向性HB-SODを開発し、これらのSODが個体レベルでの虚血再循環性不整脈、致死性不整脈、脳浮腫、あるいは内毒素性角膜潰瘍の発現を極めて有効に阻止することを示してきた。平成5年度は腎尿細管指向性AH-SOD(糸球体濾過後に近位尿細管細胞に集積)、肝細胞指向性Gal-SOD(肝細胞Galactose Receptorに特異的に結合)、およびKupffer細胞指向性Man-SOD(同細胞のMannoseReceptorに特異的に結合)を開発した。また、これらの新規SODの静脈内投与後の体内動態や組織細胞内分布動態を経時的に解析した結果、AH-SODが腎近位尿細管細胞に、GAL-SODが肝実質細胞に、MAN-SODがKupffer細胞を主体とする網内系細胞に特異的に集積する事が明かとなった。病態モデル動物で解析した結果、AH-SODが制ガン剤のシスプラチンによる腎障害を特異的に阻止軽減する事が判明した。さらに、HB-SODは虚血性脳神経障害、心筋梗塞、高血圧症(SHRおよび食塩負荷ラット)における病態を著明に改善する事が判明した。これは、HB-SODが血管局所のO_2^-による内皮依存性血管弛緩因子(NOあるいはそのSH反応産物)の不活化を阻止することにより各種の高血圧病態を改善するためであること明らかとなった。また、Mannose受容体を有する正常動物の組織細胞にMan-SODを濃縮動員すると血圧が急激かつ特異的に低下して短時間で動物が死亡することが判明した。これらの観察結果から、スーパーオキシドラジカルが病態増悪因子としてのみならず、特定の血管構成細胞を介して正常血圧を維持するための生理活性分子として不可欠な成分であることを初めて示したものである。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Edashige,K.: "Reversible priming and protein-Protein tyrosyl phosphorylation in human peripheral blood neutrophils under Hypotonic condition." Arch.Biochem.& Biophs.302(2). 343-347 (1993)
[Publications] Kanbara,T.: "Lidocaine inhibits priming and tyrosyl phosphorylation of human peripheral neutrophils" Biochem.Pharmacol.45. 1593-1598 (1993)
[Publications] Kitmura,T.: "Defective biliary excretion of epinephrine metabolites in nutant(TR-)rats:relation to the pathogenesis of black liver in the Dubin-Johnson syndrome and Corriedale sheep with an analogous excretory defect." Hepatology. 15. 1154-1159 (1993)
[Publications] Saito,D.: "Superoxide dismutase that circulates bound to albumin and accumulates in injured tissues increases survival rate of burned rars." J.Trauma. (in press). (1993)
[Publications] Saito,D.: "Direct evidence for the occurrence of reactive oxygen species in the small intestine of the burne rats." Surgery. (in press). (1993)
[Publications] Saito,D.: "Superoxide dismutase with prolonged in vivo half life inhibits intravascular hemolysis and renal injury in burned rats." Am.J.Emergency Med.11. 355-359 (1993)
[Publications] Y.Takeda: "Albumin binding superoxide dismutase with a prolonged half-life reduces reperfusion brain injury." Am.J.Physiol.264. Hl708-1716 (1993)
[Publications] K.Koyama: "In vivo determination of superoxide and asdorbyl radicals using long acting cytochrome C-and superoxide dismutase derivatives." Arch.Biochem.Biophys.(in press). (1993)
[Publications] T.Kida: "Mechanism for hypersensitvity to endotoxin in P.acnes-sensitized rats." Arch.Biochem.Biophys.(in press). (1994)
[Publications] Yamaoka,K.: "Induction of two species of superoxide dismutases in some organs of rats by low dose X-ray irradiation" Free Radical Biology & Medicine. (in press). (1994)
[Publications] Takehara,Y.: "DNA damage by various forms of active oxygens and its inhibition by different scavengers using plasmid DNA" Physiological Chemistry and Physics and Medical NMR. (in press). (1994)
[Publications] LiQ.-L.: "Preparation of Unoccupied Thyroid Hormone Receptor" Biochem.J. (in press). (1994)
[Publications] Li,Q.-L.: "Fatty Acyl-CoA Binding Activity of the Nuclear Thyroid Hormone Recepptor." j.Cell.Biochem.51. 458-464 (1993)
[Publications] 井上正康: "ストレス蛋白質-基礎と臨床" 永田和宏編中外医学社, 266 (1994)
[Publications] 佐藤英介: "“Toxicology Today"" 佐藤洋編、金芳堂,(1994)
[Publications] M.Inoue: "In L.Packer(ed.)Methods in Enzymology,Oxygen Radicals in Biological Systems." Academic Press,New York, (1994)
[Publications] M.Inoue: "In I.M.Arias(ed.)The Liver:Biology and Pathobiology" Raven Press,New York, (1994)
[Publications] K.Hirayama: "In A.Plasad(ed.)Essential and Toxic Trace Elements in Human Health and Disease." Alan RLiss Inc.,New York, (1993)

1993 Fiscal Year Annual Research Report

部位指向性SODの分子設計と活性酸代謝制御

Principal Investigator

井上 正康 大阪市立大学, 医学部, 教授 (80040278)

Research Products

[Publications] Edashige,K.: "Reversible priming and protein-Protein tyrosyl phosphorylation in human peripheral blood neutrophils under Hypotonic condition." Arch.Biochem.& Biophs.302(2). 343-347 (1993)

[Publications] Kanbara,T.: "Lidocaine inhibits priming and tyrosyl phosphorylation of human peripheral neutrophils" Biochem.Pharmacol.45. 1593-1598 (1993)

[Publications] Kitmura,T.: "Defective biliary excretion of epinephrine metabolites in nutant(TR-)rats:relation to the pathogenesis of black liver in the Dubin-Johnson syndrome and Corriedale sheep with an analogous excretory defect." Hepatology. 15. 1154-1159 (1993)

[Publications] Saito,D.: "Superoxide dismutase that circulates bound to albumin and accumulates in injured tissues increases survival rate of burned rars." J.Trauma. (in press). (1993)

[Publications] Saito,D.: "Direct evidence for the occurrence of reactive oxygen species in the small intestine of the burne rats." Surgery. (in press). (1993)

[Publications] Saito,D.: "Superoxide dismutase with prolonged in vivo half life inhibits intravascular hemolysis and renal injury in burned rats." Am.J.Emergency Med.11. 355-359 (1993)

[Publications] Y.Takeda: "Albumin binding superoxide dismutase with a prolonged half-life reduces reperfusion brain injury." Am.J.Physiol.264. Hl708-1716 (1993)

[Publications] K.Koyama: "In vivo determination of superoxide and asdorbyl radicals using long acting cytochrome C-and superoxide dismutase derivatives." Arch.Biochem.Biophys.(in press). (1993)

[Publications] T.Kida: "Mechanism for hypersensitvity to endotoxin in P.acnes-sensitized rats." Arch.Biochem.Biophys.(in press). (1994)

[Publications] Yamaoka,K.: "Induction of two species of superoxide dismutases in some organs of rats by low dose X-ray irradiation" Free Radical Biology & Medicine. (in press). (1994)

[Publications] Takehara,Y.: "DNA damage by various forms of active oxygens and its inhibition by different scavengers using plasmid DNA" Physiological Chemistry and Physics and Medical NMR. (in press). (1994)

[Publications] LiQ.-L.: "Preparation of Unoccupied Thyroid Hormone Receptor" Biochem.J. (in press). (1994)

[Publications] Li,Q.-L.: "Fatty Acyl-CoA Binding Activity of the Nuclear Thyroid Hormone Recepptor." j.Cell.Biochem.51. 458-464 (1993)

[Publications] 井上正康: "ストレス蛋白質-基礎と臨床" 永田和宏編 中外医学社, 266 (1994)

[Publications] 佐藤英介: "“Toxicology Today"" 佐藤 洋編、金芳堂,(1994)

[Publications] M.Inoue: "In L.Packer(ed.)Methods in Enzymology,Oxygen Radicals in Biological Systems." Academic Press,New York, (1994)

[Publications] M.Inoue: "In I.M.Arias(ed.)The Liver:Biology and Pathobiology" Raven Press,New York, (1994)

[Publications] K.Hirayama: "In A.Plasad(ed.)Essential and Toxic Trace Elements in Human Health and Disease." Alan RLiss Inc.,New York, (1993)

井上正康大阪市立大学, 医学部, 教授 (80040278)

[Publications] 井上正康: "ストレス蛋白質-基礎と臨床" 永田和宏編中外医学社, 266 (1994)

[Publications] 佐藤英介: "“Toxicology Today"" 佐藤洋編、金芳堂,(1994)