Partitioning of substituted phenols in liposome-water, biomembrane-water, and octanol-water systems

The effect of pH, ionic strength, and compound concentration on the liposome-water distribution ratio has been investigated for 20 chloro- and nitrophenols covering a wide range of acidities and hydrophobicities. A comparison with membrane vesicles from Rhodobacter sphaeroides shows that liposomes composed of zwitterionic phosphatidylcholine are appropriate model systems for mimicking the biomembrane-water partitioning behavior of all phenol species, i.e., neutral phenol, charged phenoxide, and ion pair. At high phenoxide concentrations,the simple partition model includes an electrostatic term for the buildup of a surface potential on the liposomes due to sorbed phenoxide. The distribution ratios of the neutral phenol species are very similar in the octanol- and the liposome-water system, but the charged phenol species partition significantly better into the anisotropic lipid bilayer than into the bulk phase octanol. The liposome-water distribution ratio is a more suitable descriptor for the uptake of a hydrophobic ionizable compound into biological membranes than the corresponding octanol-water distribution ratio. The reported data form an important base for more realistic predictions of effective phenol concentrations and phenol-to-phenoxide ratios in biological membranes, which is pivotal for assessing the toxicity, in particular, the uncoupling activity of such compounds