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

酰基辅酶a：胆固醇酰基转移酶（ACAT）与动脉硬化病变中泡沫细胞的形成密切相关。Kitasato团队建立了ACAT抑制剂高通量筛选系统，筛选了超过10000份微生物样品。结果发现了5种新的真菌代谢物，分别是purpactin、cyclodepsipeptides、glisoprenins、pyripyropenes和terpendoles。其中，pyripypypenes对A - CAT有很强的抑制作用，其微摩尔浓度IC_<50>。体内对胆固醇吸收的效果也在仓鼠身上得到了证实。因此，需要进行进一步的体内试验。pyripypypenes有望成为一种新型的抗动脉粥样硬化先导化合物。东京大学的研究小组用含有阴离子磷脂的脂质体培养小鼠腹腔巨噬细胞，建立了一个极好的泡沫细胞形成模型。利用该模型，他们发现泡沫细胞的形成被唑类抗真菌药物（酮康唑、econazole等）和甾醇衍生物阻断。在C-17或c - 20上含有氧基的类固醇可逆转胆固醇从溶酶体向内质粒网的转运。这一证据使他们能够建立一套从溶酶体运输胆固醇的测定系统。因此，溶酶体的低pH值对转运至关重要。类固醇抑制剂可能对溶酶体膜中质子驱动的胆固醇转运系统起作用。

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.