The Barrier Domain for Solute Permeation Varies With Lipid Bilayer Phase Structure

Abstract. The chemical selectivities of the transport barriers in lipid bilayers varying in composition and phase structure (gel-phase DPPC and DHPC bilayers and liquid-crystalline DPPC/CHOL/50:50 mol% bilayers) have been investigated by determining functional group contributions to transport of a series of α-substituted p-toluic acid analogs obtained in vesicle efflux experiments. Linear free energy relationships are established between the free energies of transfer for this series of compounds from water to the barrier domain and corresponding values for their transfer from water into six model bulk solvents (hexadecane, hexadecene, decadiene, chlorobutane, butyl ether, and octanol) determined in partitioning experiments to compare the barrier microenvironment to that in these model solvents. The barrier microenvironment in all bilayers studied is substantially more hydrophobic than octanol, thus establishing the location of the barrier beyond the hydrated headgroup interfacial region, as the interface is expected to be more hydrophilic than octanol. The chemical nature of the barrier domain microenvironment varies with bilayer phase structure. The barrier regions in non-interdigitated DPPC and interdigitated DHPC gel-phase bilayers exhibit some degree of hydrogen-bond acceptor capacity as may occur if these domains lie in the vicinity of the ester/ether linkages between the headgroups and the acyl chains. Intercalation of 50 mol% cholesterol into DPPC bilayers, which induces a phase transition to a liquid-crystalline phase, substantially increases the apparent barrier domain hydrophobicity relative to gel-phase bilayers to a nonhydrogen bonding, hydrocarbonlike environment resembling hexadecene. This result, combined with similar observations in liquid-crystalline egg-PC bilayers (J. Pharm. Sci. (1994), 83:1511–1518), supports the notion that the transition from the gel-phase to liquid-crystalline phase shifts the barrier domain further into the bilayer interior (i.e., deeper within the ordered chain region).

[1]  T. McIntosh,et al.  Influence of cholesterol on water penetration into bilayers. , 1982, Science.

[2]  Stephen D. Evans,et al.  Surface potential studies of alkyl-thiol monolayers adsorbed on gold , 1990 .

[3]  T. Xiang,et al.  Phase structures of binary lipid bilayers as revealed by permeability of small molecules. , 1998, Biochimica et biophysica acta.

[4]  C. Ho,et al.  Hydration and order in lipid bilayers. , 1995, Biochemistry.

[5]  V A Parsegian,et al.  Membrane dipole potentials, hydration forces, and the ordering of water at membrane surfaces. , 1992, Biophysical journal.

[6]  Ken A. Dill,et al.  Solute partitioning into chain molecule interphases: Monolayers, bilayer membranes, and micelles , 1986 .

[7]  Herman J. C. Berendsen,et al.  Simulation of Water Transport through a Lipid Membrane , 1994 .

[8]  M. Bally,et al.  Production of large unilamellar vesicles by a rapid extrusion procedure: characterization of size distribution, trapped volume and ability to maintain a membrane potential. , 1985, Biochimica et biophysica acta.

[9]  S. White,et al.  Structure of lamellar lipid domains and corneocyte envelopes of murine stratum corneum. An X-ray diffraction study. , 1988, Biochemistry.

[10]  M. E. Hoffman,et al.  Parametric analysis of membrane characteristics and membrane structure , 1983 .

[11]  R. Hartung,et al.  Phosphatidylcholine-fatty acid membranes. I. Effects of protonation, salt concentration, temperature and chain-length on the colloidal and phase properties of mixed vesicles, bilayers and nonlamellar structures. , 1988, Biochimica et biophysica acta.

[12]  O. Berger,et al.  Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. , 1997, Biophysical journal.

[13]  James H. Davis,et al.  Phase equilibria of cholesterol/dipalmitoylphosphatidylcholine mixtures: 2H nuclear magnetic resonance and differential scanning calorimetry. , 1990, Biochemistry.

[14]  W. Hubbell,et al.  The membrane dipole potential in a total membrane potential model. Applications to hydrophobic ion interactions with membranes. , 1986, Biophysical journal.

[15]  J. T. Edward,et al.  Molecular Volumes and the Stokes-Einstein Equation. , 1970 .

[16]  C. Zheng,et al.  Molecular origin of the internal dipole potential in lipid bilayers: calculation of the electrostatic potential. , 1992, Biophysical journal.

[17]  D. Worcester,et al.  Hydrostatic pressure induces hydrocarbon chain interdigitation in single-component phospholipid bilayers. , 1986, Biochemistry.

[18]  Y. Marcus.  Linear solvation energy relationships. Correlation and prediction of the distribution of organic solutes between water and immiscible organic solvents , 1991 .

[19]  H. Brockman,et al.  Dipole potential of lipid membranes. , 1994, Chemistry and physics of lipids.

[20]  R. Griffin,et al.  Comparative study of the gel phases of ether- and ester-linked phosphatidylcholines. , 1985, Biochemistry.

[21]  T. Xiang,et al.  MEAN MOLECULAR POTENTIALS IN A MODEL LIPID BILAYER: A MOLECULAR DYNAMICS SIMULATION , 1995 .

[22]  W. V. van Blitterswijk,et al.  Quantitative contributions of cholesterol and the individual classes of phospholipids and their degree of fatty acyl (un)saturation to membrane fluidity measured by fluorescence polarization. , 1987, Biochemistry.

[23]  R. Griffin,et al.  A 13C and 2H nuclear magnetic resonance study of phosphatidylcholine/cholesterol interactions: characterization of liquid-gel phases. , 1993, Biochemistry.

[24]  T R Stouch,et al.  Solute diffusion in lipid bilayer membranes: an atomic level study by molecular dynamics simulation. , 1993, Biochemistry.

[25]  T. E. Thompson,et al.  Cholesterol-induced fluid-phase immiscibility in membranes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[26]  R. Templer,et al.  Phosphatidylcholine-fatty acid membranes: effects of headgroup hydration on the phase behaviour and structural parameters of the gel and inverse hexagonal (H(II)) phases. , 1997, Biochimica et biophysica acta.

[27]  A. Leo,et al.  Partition coefficients and their uses , 1971 .

[28]  K. Pettigrew,et al.  Drug entry into the brain , 1979, Brain Research.

[29]  B. D. Anderson,et al.  Solute structure-permeability relationships in human stratum corneum. , 1989, The Journal of investigative dermatology.

[30]  Jean-François Gal,et al.  Linear Solvation Energy Relationships. Part 32. , 1986 .

[31]  S. Singer,et al.  The fluid mosaic model of the structure of cell membranes. , 1972, Science.

[32]  R. Collander,et al.  The Partition of Organic Compounds Between Higher Alcohols and Water. , 1951 .

[33]  Michael H. Abraham,et al.  Linear solvation energy relationship. 46. An improved equation for correlation and prediction of octanol/water partition coefficients of organic nonelectrolytes (including strong hydrogen bond donor solutes) , 1988 .

[34]  A. Clowes,et al.  Physical properties of lecithin-cerebroside bilayers. , 1971, Biochimica et biophysica acta.

[35]  P. Elias,et al.  Human epidermal lipids: characterization and modulations during differentiation. , 1983, Journal of lipid research.

[36]  T. Xiang,et al.  Substituent contributions to the transport of substituted p-toluic acids across lipid bilayer membranes. , 1994, Journal of pharmaceutical sciences.

[37]  A. Finkelstein,et al.  The nonelectrolyte permeability of planar lipid bilayer membranes , 1980, The Journal of general physiology.

[38]  G. R. Bartlett.  Phosphorus assay in column chromatography. , 1959, The Journal of biological chemistry.

[39]  Victor A. Levin,et al.  RELATIONSHIP OF OCTANOL/WATER PARTITION COEFFICIENT AND MOLECULAR WEIGHT TO RAT BRAIN CAPILLARY PERMEABILITY , 1980 .

[40]  T. Xiang,et al.  Transport methods for probing the barrier domain of lipid bilayer membranes. , 1992, Biophysical journal.

[41]  J. S. Hyde,et al.  Hydrophobic barriers of lipid bilayer membranes formed by reduction of water penetration by alkyl chain unsaturation and cholesterol. , 1994, Biochemistry.

[42]  T. Xiang,et al.  Permeability of acetic acid across gel and liquid-crystalline lipid bilayers conforms to free-surface-area theory. , 1997, Biophysical journal.