Xiang T X, Anderson B D
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City 84112, USA.
Biophys J. 1997 Jan;72(1):223-37. doi: 10.1016/S0006-3495(97)78661-2.
Solubility-diffusion theory, which treats the lipid bilayer membrane as a bulk lipid solvent into which permeants must partition and diffuse across, fails to account for the effects of lipid bilayer chain order on the permeability coefficient of any given permeant. This study addresses the scaling factor that must be applied to predictions from solubility-diffusion theory to correct for chain ordering. The effects of bilayer chemical composition, temperature, and phase structure on the permeability coefficient (Pm) of acetic acid were investigated in large unilamellar vesicles by a combined method of NMR line broadening and dynamic light scattering. Permeability values were obtained in distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, and dilauroylphosphatidylcholine bilayers, and their mixtures with cholesterol, at various temperatures both above and below the gel-->liquid-crystalline phase transition temperatures (Tm). A new scaling factor, the permeability decrement f, is introduced to account for the decrease in permeability coefficient from that predicted by solubility-diffusion theory owing to chain ordering in lipid bilayers. Values of f were obtained by division of the observed Pm by the permeability coefficient predicted from a bulk solubility-diffusion model. In liquid-crystalline phases, a strong correlation (r = 0.94) between f and the normalized surface density sigma was obtained: in f = 5.3 - 10.6 sigma. Activation energies (Ea) for the permeability of acetic acid decreased with decreasing phospholipid chain length and correlated with the sensitivity of chain ordering to temperature, [symbol: see text] sigma/symbol: see text, as chain length was varied. Pm values decreased abruptly at temperatures below the main phase transition temperatures in pure dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine bilayers (30-60-fold) and below the pretransition in dipalmitoylphosphatidylcholine bilayers (8-fold), and the linear relationship between in f and sigma established for liquid-crystalline bilayers was no longer followed. However, in both gel and liquid-crystalline phases in f was found to exhibit an inverse correlation with free surface area (in f = -0.31 - 29.1/af, where af is the average free area (in square angstroms) per lipid molecule). Thus, the lipid bilayer permeability of acetic acid can be predicted from the relevant chain-packing properties in the bilayer (free surface area), regardless of whether chain ordering is varied by changes in temperature, lipid chain length, cholesterol concentration, or bilayer phase structure, provided that temperature effects on permeant dehydration and diffusion and the chain-length effects on bilayer barrier thickness are properly taken into account.
溶解度 - 扩散理论将脂质双分子层膜视为一种大量脂质溶剂，渗透物必须分配到其中并扩散穿过，但该理论未能解释脂质双分子层链序对任何给定渗透物渗透系数的影响。本研究探讨了必须应用于溶解度 - 扩散理论预测的比例因子，以校正链序效应。通过核磁共振线宽展宽和动态光散射相结合的方法，在大单层囊泡中研究了双分子层化学组成、温度和相结构对乙酸渗透系数（Pm）的影响。在不同温度下，高于和低于凝胶 - 液晶相转变温度（Tm），分别在二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱和二月桂酰磷脂酰胆碱双分子层及其与胆固醇的混合物中获得了渗透率值。引入了一个新的比例因子——渗透率递减因子f，以解释由于脂质双分子层中的链序导致的渗透系数相对于溶解度 - 扩散理论预测值的降低。通过将观察到的Pm除以由大量溶解度 - 扩散模型预测的渗透系数来获得f值。在液晶相中，f与归一化表面密度σ之间存在很强的相关性（r = 0.94）：ln f = 5.3 - 10.6σ。随着磷脂链长度的减小，乙酸渗透的活化能（Ea）降低，并且当链长度变化时，与链序对温度的敏感性，即[符号：见原文]σ/符号：见原文相关。在纯二棕榈酰磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱双分子层中，在低于主要相转变温度时Pm值急剧下降（30 - 60倍），在二棕榈酰磷脂酰胆碱双分子层中低于预转变温度时下降8倍，并且不再遵循为液晶双分子层建立的ln f与σ之间的线性关系。然而，发现在凝胶相和液晶相中，ln f均与自由表面积呈负相关（ln f = -0.31 - 29.1/af，其中af是每个脂质分子的平均自由面积（单位为平方埃））。因此，只要适当考虑温度对渗透物脱水和扩散的影响以及链长度对双分子层屏障厚度的影响，就可以根据双分子层中相关的链堆积性质（自由表面积）预测乙酸的脂质双分子层渗透率，而无论链序是通过温度、脂质链长度、胆固醇浓度或双分子层相结构的变化而改变。
