Comparative Interactions of Anesthetic Alkylphenols with Lipid Membranes

Objective: While substituted phenols have a variety of pharmacological activity, the mechanism underlying their anesthetic effects remains uncertain especially about the critical target. We characterized the lipid membrane-interacting properties of different phenols by comparing with general anesthetic propofol and local anesthetics. Based on the results, we also studied the pharmacological effects possibly associated with their membrane interactivities. Methods: 1,6-Diphenyl-1,3,5-hexatriene-labeled lipid bilayer membranes were prepared with 1,2-dipalmitoylphosphatidylcholine as model membranes and with different phospholipids and cholesterol to mimic neuronal membranes. These membrane preparations were treated with phenols and anesthetics at 1 200 μM, followed by measuring the fluorescence polarization to determine the membrane interactivities to change membrane fluidity. Antioxidant effects were fluorometrically determined using diphenyl-1-pyrenylphosphine-incorporated liposomes which were treated with 10 100 μM phenols, and then peroxidized with 10 μM peroxynitrite. Results: Several phenols interacted with the model membranes and the neuronal mimetic membranes to increase their fluidity at 1 10 μM as well as lidocaine and bupivacaine did at 50 200 μM. Their comparative potencies were propofol > thymol > isothymol > guaiacol > phenol > eugenol, and bupivacaine > lidocaine, consistent with the rank order of neuro-activity. These phenols inhibited membrane lipid peroxidation at 10 and 100 μM with the potencies correlating to their membrane interactivities. Conclusion: The structure-specific membrane interaction is at least in part responsible for the pharmacology of anesthetic alkylphenols. Membrane-interacting antioxidant alkylphenols may be protective against the peroxynitrite-relating ischemia/reperfusion injury.