Structure‐Specific Membrane‐Fluidizing Effect Of Propofol

While recent studies about the pharmacological mechanism of the intravenous anaesthetic propofol (2,6-diisopropylphenol) have focused on its interaction with functional proteins, there is the possibility that propofol alters membrane properties to produce anaesthesia. In the present study, the structure-specific effects of propofol on liposomal model membranes were studied. 2. The effect of propofol on the phase transition of membrane phospholipid was analysed spectrophotometrically using 1,2-dipalmitoyl-L-alpha-phosphatidylcholine liposomes. Propofol (50-200 micromol/L) lowered the phase transition temperature to fluidize membranes. 3. Membrane fluidization was also analysed by measuring fluorescence polarization of liposomes consisting of 1,2- dipalmitoyl-L-alpha-phosphatidylcholine, 1-palmitoyl-2-oleoyl-L- alpha-phosphatidylcholine and cholesterol with different probes. Propofol fluidized all liposomal membranes in the concentration range 5-500 micromol/L by acting on both the inner and outer layers of the membranes. 4. The membrane effects of propofol were compared with those of 2,6-dialkylphenols, 1,3-dialkylbenzenes, 2-alkylphenols and alkylbenzenes. Although the membrane-fluidizing effects were shared by a series of structural analogues, propofol was most effective in fluidizing membranes, especially liposomal membranes consisting of 20 mol% cholesterol and 80 mol% 1-palmitoyl-2-oleoyl-L-alpha-phosphatidylcholine. 5. Lipophilicity was compared between propofol and its structural analogues using their capacity factors, determined by reverse-phase high-performance liquid chromatography. The potency of propofol to fluidize membranes was much greater than anticipated from its lipophilicity. 6. At 0.125-1.0 micromol/L, almost corresponding to clinically relevant concentrations, propofol significantly enhanced membrane fluidity of cholesterol-containing 1-palmitoyl-2-oleoyl-L-alpha-phosphatidylcholine liposomes. 7. These results indicate that propofol fluidizes membranes in a structure-specific manner through an interaction with membrane lipids. Such a membrane effect may be responsible for the mode of anaesthetic action of propofol.