Investigation of Novel Function and Its Relation to Diseases for New Taget Proteins to Which Sulfonylureas Bind

磺酰脲类结合的新目标蛋白的新功能及其与疾病的关系的研究

基本信息

批准号：
09470513
负责人：
NAKAYAMA Hitoshi
金额：
$ 7.04万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

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.

我们发现格列本脲（一种典型的抗糖尿病磺酰脲类药物）在心脏组织中结合并光标记 CD36，而不是磺酰脲类受体，因为它对受体的亲和力低于相应的胰腺单位。在这个项目中，我们首先旨在揭示磺酰脲类对心脏组织的功能影响。巨噬细胞中的 CD36 通过 CD36 抑制氧化 LDL 的结合、缔合和解离过程。巨噬细胞和 CD36 转染的 CHO 细胞以剂量依赖性方式抑制这些过程，但格列本脲是测试化合物中最有效的，目前我们还不清楚磺脲类是否会影响脂质代谢，然后我们研究了它们对胆固醇代谢的影响。我们发现格列本脲还抑制巨噬细胞中酰基辅酶A：胆固醇酰基转移酶（ACAT）的活性，但抑制效果并非如此。与典型的 ACAT 抑制剂 CI-976 和 NTE-122 一样有效，但在 100 μM 格列本脲存在下，抑制作用是完全的。这些结果表明，磺酰脲类药物不仅可以作为通过 CD36 摄取氧化 LDL 的抑制剂，而且可以作为 ACAT 抑制剂。尽管化学结构与传统抑制剂有很大不同，但这表明它们可以成为产生新的脂质代谢潜在抑制剂的种子。