Trifluoperazine induces domain formation in zwitterionic phosphatidylcholine but not in charged phosphatidylglycerol bilayers

Abstract

The interaction of trifluoperazine with the zwitterionic lipids dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine and with anionic dimyristoylphosphatidylglycerol was studied by means of microcalorimetry and fluorescence spectroscopy. Intercalation of drug molecules into the lipid bilayers was confirmed by the observed differential scanning calorimetry peak broadening and the decrease in chain-melting temperatures. For trifluoperazine:lipid mole ratios higher than 0.4 and 0.6 (for dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine, respectively) the deconvolution of transition profiles into two Gaussian components was possible, which suggests phase separation in the studied mixtures. Deconvolution of the thermograms was not possible for any of the drug:dimyristoylphosphatidylglycerol mole ratios studied. To confirm the existence of phase separation in trifluoperazine-phosphatidylcholine mixtures fluorescence spectroscopy experiments were performed using Laurdan as a probe. From the generalised polarisation versus excitation wavelength dependences, recorded at different temperatures, we conclude that a phase separation occurs in the gel state of the studied trifluoperazine-phosphatidylcholine mixtures. We attribute the existence of domains in the bilayer to the dissimilar interactions of two protonation forms of trifluoperazine with phosphatidylcholine molecules. Structural defects present at domain boundaries could be related to the trifluoperazine induced increase of membrane permeability and fluidity. This may partially explain the mechanism of multidrug resistance modulation by trifluoperazine.

Phase separation is induced by phenothiazine derivatives in phospholipid/sphingomyelin/cholesterol mixtures containing low levels of cholesterol and sphingomyelin

“…As we have shown some years ago phenothiazine derivative -trifluoperazine, can induce phase separation in phosphatidylcholine bilayers in temperatures below the main phase transition [11]. The fact that phenothiazines alter the properties of lipid bilayers may correlate with their ability to modulate the activity of multidrug-related transport proteins [12] and therefore they became the object of our studies.…”

“…Recently the new parametergeneralized polarization slope (GPS) was also proposed for quantitative description of phase properties of lipid systems in which GP(λ ex ) dependence is linear [22]. Few years ago we used Laurdan generalized polarization to monitor the influence of TFP on the phase behavior of synthetic phosphatidylcholines: DPPC and DMPC [11]. In this work we observed that when bilayers were in the gel state the addition of trifluoperazine induced phase separation.…”

Interaction of the Macrolide Antibiotic Azithromycin with Lipid Bilayers: Effect on Membrane Organization, Fluidity, and Permeability

“…Examples include anesthetics (7,8), cyclosporine (9), steroids (10), trifluoroperazine (11), and antibiotics like aminoglycosides (12) or macrolides (azithromycin) (13). This latter compound was also shown to markedly inhibit endocytosis (14,15), probably by interacting with lipids, modifying biophysical properties of membrane and affecting membrane dynamics in living cells (13).…”

The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

“…It has been demonstrated that cis- (76) and trans-flupentixol (75) (see Fig. 5) inhibited the photoaffinity labeling of P-gp by substrate analogues [173].…”

“…Besides CPZ (9), TFP (5) is another phenothiazine derivative whose interaction with membranes is relatively well known. In the extensive study of Hendrich et al [76], the influence of TFP (5) on model membranes formed from zwitterionic lipids (DMPC and DPPC) and negatively charged dimyristoylphosphatidylglycerol (DMPG) was investigated by means of DSC and fluorescence spectroscopy. For all lipids lowering of T m , calorimetric peak broadening, and ∆H decrease were recorded in the presence of the drug.…”