Phenothiazines, derivatives, membrane

Dixon and Mountain reported that exposure of mice to ozone at 1 ppm for 5 h resulted in a depletion of lung histamine content to as low as 75% of the control value 5 days later. They also observed that pretreatment with promethazine, an antihistaminic agent, resulted in a decrease in the amount of pulmonary edema produced by a sublethal dose of ozone. However, promethazine, in addition to being a potent antihistaminic agent, is a phenothiazine derivative and thus might act to trap fiee radicals or stabilize membranes. 

Influence of Phenothiazine Derivatives and Flavonoids on Properties of Model and Natural Membranes... 

The interactions of TDZ (6) with model membranes composed of different phospholipids were also studied by the same group [78]. Calorimetric studies demonstrated that TDZ (6) altered the thermotropic properties of negatively charged DMPC membranes to a larger extent than of zwitterionic phospholipids (PC and PE). The character of the drug-induced changes of the transition parameters of all studied lipids indicated that TDZ (6), similarly to other phenothiazine derivatives, was likely to be localized close to the po-lar/apolar interface of the bilayers. Experiments in which fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was employed revealed that TDZ (6) reduced the mobility of lipid molecules in a concentration-dependent manner and thus decreased membrane fluidity. The influence of TDZ (6) on isolated... 

The newly synthesized phenothiazine derivative 2-trifluoromethyl-10-[4-(methanesulfonylamido)butyl]-phenothiazine (FPhMS, see Fig. 1 for chemical structure) was also extensively studied in the context of its interaction with lipid bilayers. DSC was used to study the influence of this compound on model membranes formed from DMPE [80], DPPC [81], DMPC, and DMPG [82]. In all the studied lipid systems FPhMS (16) lowered Tm, caused broadening of transition peaks, and induced the decrease of AH. Melting temperatures were found to be reduced by the phenothiazine derivative to a similar extent when different lipids possessing acyl chains of the same length were compared. 

At high concentrations phenothiazine derivatives are known to induce erythrocyte hemolysis. Many groups studied this process parameters such as hemolysis onset, 50%, and completion have been widely used to characterize phenothiazine-induced membrane disruption. TFP (5) was reported to... 

The potassium channels present in neuronal membranes could also be affected by phenothiazine derivatives. In the study performed by Ogata et al. [255] it was shown that CPZ (9) interfered with several types of potassium channels present in membranes of neurons of the newborn rat cultured dorsal root ganglia. Reversible reduction of the amplitude was found for transient and delayed rectified K+ currents, while inward rectified K+ current remained unaffected by CPZ (9). The block of delayed rectified K+ current by CPZ (9) was, however, less potent than block of the transient one. The hyper-polarizing shift of the steady-state inactivation curve for transient K+ current indicated that CPZ (9) binds preferably to the channels in the inactivated state. 

Apart from causing very well known cardiotoxic effects, phenothiazine derivatives can accumulate in lung epithelial cell membranes and therefore cause severe respiratory disorders. In the study performed by Ito et al. [279] it was found that CPZ (9) inhibited transepithelial Cl transport, mainly due to two mechanisms influence on the beta-adrenergic receptor and inhibition of basolateral potassium channels. The authors of this study also suggested that the recorded effects could result from the electrostatic interactions between the drug molecules and negatively charged components of the inner leaflet of the plasma membrane. 

Large conductance chloride channels (Maxi Cl channels) present in membranes of fibroblast cells were another class of chloride channels that were affected by the presence of phenothiazine derivatives. As described by Valverde et al. [280], these channels become activated by CPZ (9) and tri-flupromazine (11). Activation was dose-dependent for both drugs the half-maximal responses (EC50) were 21 and 23 iM for CPZ (9) and triflupro-mazine (11), respectively. The effects of the drugs were observed exclusively for applications in the extracellular bathing solution. The authors of this paper provided no information about the possible physiological role of Maxi Cl channel activation by phenothiazine drugs. 

These phenomena may be explained in terms of hepatic lysosomal membrane change induced by the chemicals (suggested by recent work with phenothiazine derivatives), or in terms of stress and adrenocortical intervention, or of adaptive enzyme power of the liver. 

The phosphorescence of trivalent cations (as analogues of Ca ) is also widely used in binding studies. The photobinding of phenothiazine derivatives has been studied for different types of biological membranes. The specificity of binding is low, although general, and can be used to identify and localize membrane proteins. The influence of Ca " and phase behaviour in synaptosomal lipids have been examined by the steady-state fluorescence polarization of A fluorescent probe of the tumour promoter phorbol... 

Hendrich et al. [155] investigated the mechanism of incorporation of phe-nothiazines in the membrane bilayer lipids. They studied the influence of a particular phenothiazine derivative, TFZ, on the thermal properties of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylethanolamine by microcalorimetry. The main phase transition of both lipids was affected by this drug, depending on its concentration. The results suggest that TFZ was probably incorporated into both dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylethanolamine bilayers. The phase separation was presumably induced by the different modes of the drug-bilayer interactions of protonated and unprotonated forms of TFZ. Only phosphatidylcholine, which possesses polar heads less densely packed in bilayers than phosphatidylethanolamine ones, was able to distinguish between the different protonated forms of TFZ. 

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