| Project/Area Number |
02452267
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
SUGIYAMA Yuichi (1991) Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (80090471)
花野 学 (1990) 東京大学, 薬学部, 教授 (60012598)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Hiroshi Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (80206523)
澤田 康文 東京大学, 医学部, 助教授 (80114502)
杉山 雄一 東京大学, 薬学部, 助教授 (80090471)
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| Project Period (FY) |
1990 – 1991
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| Project Status |
Completed (Fiscal Year 1991)
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| Budget Amount *help |
¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 1991: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1990: ¥4,600,000 (Direct Cost: ¥4,600,000)
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| Keywords | receptor-mediated endocytosis / epidermal growth factor (EGF) / down-regulation / internalization |
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| Research Abstract |
Pharmacokinetic analysis of the tissue distribution of EGF in rats performed in vivo clarified that the uptake of EGF by the liver and kidney exhibited clear saturation with Km values of 7 nM and 0.4 nM, respectively, and that both tissues could account for more than 80 % of the total plasma clearance of EGF in the distribution phase. The hepatic and renal handlings of EGF by isolated perfused organds were analyzed to obtain the kinetic parameters with respect to receptor-mediated endocytosis (RME). In the overall RME process in the liver, the EGF-receptor association and dissociation processes are rapid (mean time<l min), the degradation process is much slower (mean time 4-5 h) and the internalization process is intermediated (mean time 4-5 min). The mean time required for the recovery of receptors after being down-regulated in the liver is approx. 30 min, and was much shorter than those in other tissues. Such rapid recovery from the receptor down regulation in the liver reflects the process of recycling of internalized EGF receptors to the cell surface. The kinetic parameters obtained from the perfused livers and from isolated hepatocytes were compared, and a significant difference was observed only for the association rate constant (kon). A hypothesis accounting for this difference is proposed, in which the association rate of EGF to the cell surface receptor is considered to be limited by the diffusion in the unstirred water layer in the interstitial space of the intact liver such as the perfused liver. The comparison of EGF handling between the filtering and nonfiltering perfused kidneys demonstrated that the bulk of receptor-mediated EGF uptake takes place via the antiluminal plasma membrane with very high affinity (kd=0.1 nM).
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