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Dipole Potential and Head-Group Spacing Are Determinants for the Membrane Partitioning of Pregnanolone

Helsinki Biophysics & Biomembrane Group, Institute of Biomedicine/Biochemistry, Biomedicum, University of Helsinki, Helsinki, Finland (J.-M.I.A., T.S., J.M.H., P.K.J.K.); Department of Ophthalmology, University of Helsinki, Helsinki, Finland (J.M.H.); and Memphys—Center for Biomembrane Physics, Odense, Denmark (P.K.J.K.)

The membrane interactions of pregnanolone, an intravenous general anesthetic steroid, were characterized using fluorescence spectroscopy and monolayer technique. di-8-ANEPPS [4-[2-[6-(dioctylamino)-2-naphthalenyl]ethenyl]-1-(3-sulfopropyl)-pyridinium], a membrane dipole potential ()-sensitive probe, revealed pregnanolone to decrease similarly as reported previously for other anesthetics. The decrement in was approximately 16 and 10 mV in dipalmitoylphosphatidylcholine (DPPC) and DPPC/cholesterol (90:10, mol/mol) vesicles, respectively. Diphenylhexatriene anisotropy indicated pregnanolone to have a negligible effect on the acyl chain order. In contrast, substantial changes were observed for the fluorescent dye Prodan, thus suggesting pregnanolone to reside in the interfacial region of lipid bilayers. Langmuir balance studies indicated increased association of pregnanolone to DPPC monolayers containing cholesterol or 6-ketocholestanol at surface pressures > 20 mN/m as well as to monolayers of the unsaturated 1-palmitoyl-2-oleoylphosphatidylcholine. In the same surface pressure range, the addition of phloretin, which decreases , reduced the penetration of pregnanolone into the monolayers. These results suggest that membrane partitioning of pregnanolone is influenced by the spacing of the phosphocholine head groups as well as by membrane dipole potential. The latter can be explained in terms of electrostatic dipole-dipole interactions between pregnanolone and the membrane lipids with their associated water molecules. Considering the universal nature of these interactions, they are likely to affect membrane partitioning of most, if not all, weakly amphiphilic drugs.

Address correspondence to: Dr. Juha-Matti Alakoskela, Helsinki Biophysics and Biomembrane Group, Institute of Biomedicine/Biochemistry, University of Helsinki, P.O. Box 63, FIN-00014, Haartmaninkatu 8, Helsinki, Finland. E-mail: juha-matti.alakoskela{at}helsinki.fi

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