Cytotoxicity of phenothiazine derivatives associated with mitochondrial dysfunction: A structure-activity investigation. (1st April 2015)

• Record Type: Journal Article
• Authors: de Faria, Priscila A.; Bettanin, Fernanda; Cunha, Rodrigo L.O.R.; Paredes-Gamero, Edgar J.; Homem-de-Mello, Paula; Nantes, Iseli L.; Rodrigues, Tiago
• Is Part Of: Toxicology. Volume 330(2015)
• Page Start: 44
• Page End: 54
• Publication Date: 2015-04-01
• Subjects: CMF-BSS calcium- and magnesium-free buffered saline solution -- CPZ chlorpromazine -- DMEM Dulbecco's modified Eagle'medium -- EC50 half maximal effective concentration -- FP fluphenazine -- HTC hepatoma tissue culture -- IMP imipramine -- LDH lactate dehydrogenase -- MPT mitochondrial permeability transition -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide -- O/W n-octanol/water -- PHT phenothiazinic nucleus -- PI propidium iodide -- PTZ phenothiazine derivative -- TFP trifluoperazine -- TFPZ triflupromazine -- TR thioridazine -- ΔΨ mitochondrial transmembrane potential -- DFT density functional theory; HTC cells -- Cytotoxicity -- Mitochondrial permeability transition -- Phenothiazine -- Cell death -- Structure-activity; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2015.02.004
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: Phenothiazines induced cell death in a concentration dependent manner in HTC cells. Structural requirements that account to phenothiazine cytotoxicity were determined. Phenothiazines promote immediate morphological changes in cultured liver cells. Phenothiazine-induced cell death was accompanied of plasma membrane permeabilization. The dissipation of mitochondrial membrane potential and permeabilization correlated with cytotoxicity. Abstract: Phenothiazine derivatives are neuroleptic drugs used in the treatment of schizophrenia and anxiety. Several side effects are described for these drugs, including hepatotoxicity, which may be related to their cytotoxic activity. Working with isolated rat liver mitochondria, we previously showed that phenothiazine derivatives induced the mitochondrial permeability transition associated with cytochrome c release. Since the mitochondrial permeabilization process plays a central role in cell death, the aim of this work was to evaluate the effects of five phenothiazine derivatives (chlorpromazine, fluphenazine, thioridazine, trifluoperazine, and triflupromazine) on the viability of hepatoma tissue culture (HTC) cells to establish the structural requirements for cytotoxicity. All phenothiazine derivatives decreased the viability of the HTC cells in a concentration-dependent manner and exhibited different cytotoxic potencies. The EC50 values ranged from 45 to 125 μM, with the piperidinic derivative thioridazine displaying the most cytotoxicity, followed by the piperazinic and aliphatic derivatives. The addition of the phenothiazine derivatives to cell suspensions resulted in significant morphological changes and plasma membrane permeabilization. Octanol/water partition studies revealed that these drugs partitioned preferentially to the apolar phase, even at low pH values (≤4.5). Also, structural and electronic properties were calculated employing density functional theory. Interestingly, the phenothiazine derivatives promoted an immediate dissipation of the mitochondrial transmembrane potential in HTC cells, and the EC50 values were closely correlated with those obtained in cell viability assays, as well as the EC50 for swelling in isolated mitochondria. These results significantly contribute to improving our understanding of the specific structural requirements of the phenothiazine derivatives to induce cell death and suggest the involvement of the mitochondrial permeability transition in phenothiazine-induced cytotoxicity in HTC cells.