Partitioning of Substituted Phenols in Liposome−Water, Biomembrane−Water, and Octanol−Water Systems

Abstract

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.