Effect of chlorpromazine and trifluoperazine on cytoskeletal components and mitochondria in cultured mammalian cells

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.