Inhibition of foam cell formation : Application to the discovery of novel antiatherosclerotic agents

酰辅酶A：胆固醇酰基转移酶(ACAT)与动脉粥样硬化病变中泡沫细胞的形成密切相关。Kitasato Group建立了ACAT抑制剂的高通量筛选系统，并筛选了10,000多个微生物样本。结果发现了5种新的真菌代谢物，分别是紫杉素、环多肽、甘油三烯、吡喃和萜内酯。其中，吡啶类化合物表现出很强的抑制A CAT活性，其IC50&gt；值为名摩尔水平。在仓鼠身上也证明了体内吸收胆固醇的效果。因此，应该做进一步的体内试验。吡喃类化合物有望成为一种新型的抗动脉粥样硬化的先导化合物。东京建立了一个极好的泡沫细胞形成模型，用含有阴离子磷脂的脂质体孵育小鼠腹膜巨噬细胞。利用该模型，他们发现，唑类抗真菌药物(酮康唑、益康唑等)和甾醇衍生物可以阻止泡沫细胞的形成。C-17或20位含氧基团的类固醇可逆转地抑制特定胆固醇从溶酶体向内质网的转运。这一证据使他们能够建立一种从溶酶体内转运胆固醇的检测系统。因此，溶酶体中的低pH值是运输所必需的。类固醇抑制剂可能对溶酶体膜上的质子驱动的胆固醇运输系统起作用。

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.