Niikura Kazuaki
Data Management & Regulatory Support Department, Astellas Research Service Co., Ltd., Ibaraki, Japan.
Drug News Perspect. 2006 Apr;19(3):139-44. doi: 10.1358/dnp.2006.19.3.977442.
Vacuolar ATPases (V-ATPases) are present not only in the plasma membranes of specialized cells but also in ubiquitous intracellular acidic compartments, which are essential for physiological cellular function. Consequently, although V-ATPases are important etiologically in several diseases, it seems that they might not be good molecular targets. In fact, bafilomycin A1, a potent and specific inhibitor of V-ATPase, exerts severe and acute toxic reaction when administered to animals. On the other hand, disruption of subunit a3 of V-ATPase is not embryonic lethal, but knockout mice merely exhibit osteopetrosis due to loss of osteoclastic bone resorption. In addition, recent studies have demonstrated that novel V-ATPase inhibitors, which have inhibition selectivity, can be systemically administered to animals and are highly efficacious against bone loss in lytic bone disease models. Therefore, the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is their selectivity in the inhibition.
液泡型ATP酶（V-ATP酶）不仅存在于特化细胞的质膜中，也存在于普遍存在的细胞内酸性区室中，这些区室对细胞的生理功能至关重要。因此，尽管V-ATP酶在几种疾病的病因学中很重要，但它们似乎不是理想的分子靶点。事实上，巴弗洛霉素A1是一种强效且特异性的V-ATP酶抑制剂，给动物施用时会产生严重的急性毒性反应。另一方面，V-ATP酶亚基a3的缺失并非胚胎致死性的，但敲除小鼠仅因破骨细胞骨吸收丧失而表现出骨质石化。此外，最近的研究表明，具有抑制选择性的新型V-ATP酶抑制剂可以全身给药于动物，并且在溶骨性骨病模型中对骨质流失具有高效性。因此，关于V-ATP酶抑制剂治疗效用的关键问题在于它们抑制作用的选择性。
