| Project/Area Number |
09470513
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
医薬分子機能学
|
|---|
| Research Institution | Kumamoto University |
|---|
Principal Investigator |
NAKAYAMA Hitoshi Kumamoto University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (70088863)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KUNIYASU Akihiko Kumamoto University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 教務員 (90241348)
KAI Hirofumi Kumamoto University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (30194658)
ISHIZUKA Tadao Kumamoto University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (60176203)
|
|---|
| Project Period (FY) |
1997 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥11,000,000 (Direct Cost: ¥11,000,000)
Fiscal Year 1999: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1997: ¥5,000,000 (Direct Cost: ¥5,000,000)
|
|---|
| Keywords | sulfonylureas / glibenclamide / macrophage / CD36 / ACAT / cholesterol metabolism / atherosclerosis / 光アフィニティラベル / スカベンジャー受容体 |
|---|
| Research Abstract |
We found out that glibenclamide, a typical antidiabetic sulfonylurea, bound and photolabel CD36 instead of sulfonylurea receptors in cardiac tissues, since its affinity for the receptors was lower than the corresponding pancreatic counterparts. In this project we first aim to reveal functional effects of sulfonylureas on CD36 in macrophages. Glibenclamide inhibited the binding, association, and dissociation processes of oxidized LDL via CD36 in macrophages and CD36-transfected CHO cells in dose-dependent manners. Other sulfonylureas also inhibited those processes but glibenclamide was the most effective among the compounds tested. Little has been known whether sulfonylureas affect the lipid metabolism and we then investgated their effects on cholesterol metabolism. We discovered that glibenclamide also inhibited the activity of acyl CoA: cholesterol acyltransferase (ACAT) in macrophages. The inhibition was not so much effective as those by CI-976 and NTE-122, typical ACAT inhibitors but the inhibition was complete in the presence of 100 μM glibenclamide. These results indicate that sulfonylureas act as not only inhibitor for oxidized LDL uptake via CD36 but also ACAT inhibitor, although chemical structures are quite different from conventional inhibitors, suggesting that they can be seeds to generate new potential inhibitors for the lipid metabolism.
|
