Structure-specific membrane-fluidizing effect of propofol.
1. 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.
Department of Dental Pharmacology, Asahi University School of Dentistry, Hozumi, Gifu, Japan. hiro@dent.asahi-u.ac.jp
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Tsuchiya
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D018686:Anesthetics, Intravenous / Q000737:chemistry / Q000494:pharmacology*; D008560:Membrane Fluidity / Q000187:drug effects* / Q000502:physiology; D008563:Membrane Lipids / Q000737:chemistry*; D008567:Membranes, Artificial; D015742:Propofol / Q000031:analogs & derivatives / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D018686:Anesthetics, Intravenous; D008563:Membrane Lipids; D008567:Membranes, Artificial; D015060:1,2-Dipalmitoylphosphatidylcholine; D015742:Propofol