The Evaluation of Liposome-Water Partitioning of 8-Hydroxyquinolines and Their Copper Complexes

Abstract

Bioavailability and toxicity of mixtures are urgent research issues, but usually mixtures of exclusively organic chemicals or exclusively metals are investigated. In our study, we explored the role of combinations of hydrophobic ionogenic organic compounds (HIOCs) with copper (Cu2+)for uptake and bioavailability of metals and hydrophobic metal complexes in an in vitro membrane system. We investigated the influence of the interactions of copper and 8-hydroxyquinolines, both components used in formulations of pesticides, on their partitioning into liposomes, which are model systems for biological membranes and are composed of lipid bilayers made of phosphatidylcholine. The test set of compounds comprised the parent compound 8-hydroxyquinoline and 8-hydroxyquinolines with hydrophobic (e.g., 5-chloro-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline) and with hydrophilic (e.g., 8-hydroxyquinoline-5-sulfonic acid) substituents. Hydrophobic 8-hydroxyquinolines facilitate the passive uptake of copper into phospholipid bilayers by complex formation. Not only the neutral species of the ligands and their neutral copper ligand complexes are significantly taken up into the membrane, but also the cationic and anionic species of the ligands and the cationic complexes. The neutral, anionic, and cationic species of 8-hydroxyquinoline and the hydrophobic substituted 8-hydroxyquinolines exhibit linear correlations between their logarithmic liposome-water partitioning coefficients (log Klipw) and the logarithmic octanol-water partitioning coefficients of their neutral species (log Kow, neutral). The neutral species show the strongest partitioning followed by the anionic and cationic species. The associated quantitative structure activity relationships describing the dependency of log Klipw of the various species from log Kow, neutral of the neutral ligand species have slopes between 0.9 and 1. In contrast, the partitioning of the neutral and cationic copper-8-hydroxyquinoline complexes is dependent on several factors including the hydrophobicity of the ligand, the effective molecular size, and the polarization of the complex itself. In consequence, there is no linear relationship between log Klipw of these complexes and log Kow of the neutral species of their ligands. The complexes with very bulky substituents showed a reduced uptake. The Klipw of the nominally neutral complexes, where Cu2+ is coordinated with two ligands, were a factor three to four higher than the Klipw of the positively charged complexes with only one ligand. Although liposome-water partitioning merely describes one element of the uptake process into biological membranes, it is a key process for bioavailability of hydrophobic compounds and, presumably, also plays a crucial role for biological uptake of the described metal organic complexes.