Dudani A K, Gupta R S
Tissue Cell. 1987;19(2):183-96. doi: 10.1016/0040-8166(87)90004-8.
Antipsychotic drugs such as chlorpromazine and trifluoperazine have been implicated to mediate their action by inhibiting calmodulin, the general calcium regulatory protein in eukaryotic cells. We observed that both these drugs were cytotoxic to different mammalian cell types at concentrations two- to three-fold lower than those required to inhibit calmodulin-dependent phosphodiesterase activity. These drugs also caused shrinkage and rounding of chicken embryo fibroblast cells without affecting any of the cytoskeletal components, viz. microtubules, microfilaments and intermediate filaments. However, at physiological concentrations of these drugs, a major change was observed in mitochondria which assumed rounded and swollen shapes and concentrated towards the perinuclear region of cells. These studies provide evidence that in contrast to earlier reports, cytoskeletal components are not the primary targets of these drugs. It is suggested that mitochondria may be one of the first structures to be affected by these drugs and the consequent energy depletion may lead to the other observed effects.
诸如氯丙嗪和三氟拉嗪之类的抗精神病药物被认为是通过抑制钙调蛋白来介导其作用的，钙调蛋白是真核细胞中的一种通用钙调节蛋白。我们观察到，这两种药物对不同的哺乳动物细胞类型具有细胞毒性，其浓度比抑制钙调蛋白依赖性磷酸二酯酶活性所需的浓度低两到三倍。这些药物还导致鸡胚成纤维细胞收缩和变圆，而不影响任何细胞骨架成分，即微管、微丝和中间丝。然而，在这些药物的生理浓度下，观察到线粒体发生了重大变化，线粒体呈现圆形和肿胀形状，并向细胞的核周区域聚集。这些研究提供了证据，表明与早期报告相反，细胞骨架成分不是这些药物的主要靶点。有人提出，线粒体可能是最早受到这些药物影响的结构之一，由此导致的能量消耗可能会引发其他观察到的效应。
