| Project/Area Number |
06557128
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 試験 |
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| Research Field |
Biological pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
INOUE Keizo Faculty of Pharmaceutical Sciences, University of Tokyo, Proffesor, 薬学部, 教授 (30072937)
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| Co-Investigator(Kenkyū-buntansha) |
SAEKI Takao Eisai Co, LTD,Tukuba, Research Lab., Senior Reseacher, 研究開発本部, 主任研究員
TOMODA Hirosi Reserch Center for Biological function, The Kitasato Institute, Chief Director, 細胞化学研究部, 副部長 (70164043)
AOKI Junken Faculty of Pharmaceutical Sciences, University of Tokyo, Assistant Proffesor, 薬学部, 助手 (20250219)
ARAI Hiroyuki Faculty of Pharmaceutical Sciences, University of Tokyo, Assosiate Proffesor, 薬学部, 助教授 (40167987)
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| Project Period (FY) |
1994 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 1996: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1995: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1994: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | Choresterol / CETP / HDL / LDL / Macropage / SRBI / スカベンジャー受容体 / 変性LDL / リポ蛋白質 / ライソソーム / トランスポート / 動脈硬化 / アポE / ホスファチジルコリン / スフィンゴミエリン |
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| Research Abstract |
The lipid-laden foam cells that are typically found in atherosclerotic lesions in the arterial wall are believed to be derived, at least in part, from tissue macrophages that have become engorged with cholesteryl ester-rich lipoproteins. Tissue macrophages themselves are derived from circulating blood monocytes that have entered the subendotherial space. Although the mechanism for the conversion of a subendotherial monocyte to a foam cell is not fully understood, one process that has been proposed to contribute to the accumulation of cellular cholesteryl ester in these cells is the scavenger receptor pathway.
The agents which inhibit cholesteryl ester accumulation in macrophages should be useful in both elucidating mechanism involved in foam cell formation and developing pharmacological drugs to prevent the formation of atherosclerotic plaques. A series of antimycotics were reported to have substantial effects on cellular cholesterol metabolism. The data obtained in the present study de
… More
monstrate that one of the antimycotics, ketoconazole, effectively inhibit cholesteryl ester synthsis by restricting the movement of endocytosed cholesterol from lysosomes to other cellular sites.
In addition, various steroid derivertives were assessed for their ability to inhibit the cholesteryl ester formation from endocytosed cholesterol by macrophages. Among various steroids tested, one group of steroids having an oxo group at the C17 or C20 position such as pregnenolone, progesterone, androstenedione, and dehydroisoandrosterone completely inhibited cholesteryl ester formation at 10 muM.In contrast, other group of steroids having a hydroxy group at the C17 position such as testosterone and androstenediol had a lesser effect ; complete inhibition for cholesteryl ester formation was achieved at 100 muM or more. The mechanism for the inhibition by the former class of steroids was further studied. These steroids did not block the uptake or lysosomal hydrolysis of liposomes, nor esterification of fatty acyl chains into triacylglycerols. Upon incubation with the steroids having an oxo group at the C17 or C20 position. free cholesterol taken up by the macrophages is likely to be accumulated in phagocytotic vacuoles from cytochemical observation with filipin-cholesterol staining. These results indicate that a series of structurally-related steroids characterized by the presence of an oxo group at the C17 or C20 position inhibit cholesteryl ester formation in macrophages by blocking the intracellular transport of endocytosed cholesterol from lysosomes to endoplasmic reticulum. Less
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