| Project/Area Number |
02557094
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | The Kitasato Institute |
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Principal Investigator |
OMURA Satoshi The Kitasato Institate President, 所長 (90050426)
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| Co-Investigator(Kenkyū-buntansha) |
ARAI Hiroyuki Univ. Tokyo, Pharmaceutical Sci. Assit. Prof., 薬学部, 助手 (40167987)
KUDO Ichiro Univ. Tokyo, Pharmaceutical Sci. Assoc. Prof., 薬学部, 助教授 (30134612)
TOMODA Hiroshi The Kitasato Institute, RCBF Chief Researcher, 生物機能研究所, 室長 (70164043)
奥田 重信 北里研究所, 研究部, 部長 (30013296)
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| Project Period (FY) |
1990 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 1992: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1991: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1990: ¥6,400,000 (Direct Cost: ¥6,400,000)
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| Keywords | macrophage / foam cell / ACAT / ACAT inhibitor / azole / steroid / cholesterol / cholesterol transport / グリソプレニン / ピリピロペン / マクロファ-ジ / シクロデプシペプチド / 抗真菌剤 / 阻害剤 / パ-パクチン / コレステロ-ル / 細胞内輸送 |
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| Research Abstract |
Acyl-CoA: cholesterol acyltransferase (ACAT) is closely involved in the foam cell formation in aterolsclerotic lesion. Kitasato group established a high throughput screening system for ACAT inhibitors and screened over 10,000 microbial samples. As a result, five kinds of novel fungal metabolites were discovered, namely, purpactins, cyclodepsipeptides, glisoprenins, pyripyropenes and terpendoles. Among them, pyripyropenes showed very potent A CAT inhibition with namomolar level of IC_<50> values. The in vivo efficacy for cholesterol absorption was also demonstrated using hamsters. Therefore, further in vivo tests should be done. Pyripyropenes are expected to be a new type of lead compounds working against atherosclerosis.
The group of Univ. Tokyo established an excellent model of foam cell formation using mouse peritoneal macrophages incubated with liposomes containing anionic phospholipids. Utilizing the model, they found that foam cell formation was blocked by azole antifungal drugs (Ketoconazole, econazole etc) and sterol derivatives. The steroids having an oxo-group at C-17 or 20 reversively inhibited the specific cholesterol transport from lysosomes to endoplasmicr reticulum. This evidence permitted them to establish an assay system for cholesterol transport from lysosomes. As a result, low pH in lysosomes is essential for the transport. The steroid inhibitor may work against the proton-driven cholesterol transport system in the lysosomal membrane.
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