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Polar-group behaviour in mixed monolayers of phospholipids and fusogenic lipids.

ABSTRACT: 1. The surface potentials of mixed monolayers of synthetic phospholipids with lipids that are fusogenic for hen erythrocytes were investigated. 2. At pH 5.6 and 10, but not at pH2, mixed monolayers of the fusogenic lipid, glycerol mono-oleate, with phosphatidylcholine exhibited negative deviations from the ideality rule in surface potential per molecule which were accompanied by negative deviations in mean molecular area. 3. Interactions of this type were not seen with chemically related but non-fusogenic lipids, nor were they found in mixed monolayers of any of the lipids with phosphatidylethanolamine. 4. Experiments with dihexadecyl phosphate and hexadecyltrimethyl-ammonium indicated that the complete head group of phosphatidylcholine is required for its observed behaviour with fusogenic lipids. 5. Bivalent cations (Ca2+, UO2(2+) or Zn2+) in the subphase at pH 5.6 significantly modified the behaviour of mixed monolayers of fusogenic lipids with phospholipids; there was a parallel perturbing effect of fusogenic lipids on interactions between monolayers of phospholipids and bivalent cations. 6. Possible molecular interactions of fusogenic lipids with membrane phospholipids, and the role of Ca2+, are discussed which may be relevant to cell fusion in erythrocytes induced by low-melting lipids in the presence of Ca2+.

SUBMITTER: Maggio B

PROVIDER: S-EPMC1172841 | biostudies-other | 1976 May

REPOSITORIES: biostudies-other

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Project description:The intracellular unbound drug concentration (Cu,cell) drives pharmacological and toxicological responses for targets inside cells. We have previously shown that Cu,cell is not always equal to extracellular unbound drug concentrations (e.g. plasma concentrations). However, the underlying mechanisms that drive cellular drug binding are poorly understood. The aim of this study was to evaluate drug binding to individual cellular components, such as neutral lipids (NL) and phospholipids (PL). The fibroblastic 3T3-L1 cell line was used as a cellular model. The cells were either used as wild-type (WT cells) or were treated with a differentiation cocktail that induced an adipocyte-like phenotype with large NL droplets (NL+PL+ cells), or treated with propranolol to induce accumulation of PL (PL+ cells). The three cell types were analysed for morphology, global protein expression, lipid content, cellular volume and lysosomal appearance. The cells were exposed to 23 drugs with diverse physicochemical properties, e.g., with regard to lipophilicity, charge, molecular weight and polar surface area. The cellular binding (fu,cell) and the total accumulation ratio (Kp) were measured and used to obtain the intracellular bioavailability (Fic)—defined as the unbound fraction of the drug concentration added to the cells that is available for intracellular target interaction. The NL+PL+ cells had an adipocyte-like morphology, whereas the PL+ were not visually distinguishable from WT cells. Analysis of the global proteome combined with pathway analysis supported the morphological appearances and confirmed the adipocyte-like phenotype of NL+PL+ cells and the normal morphology of PL+ cells. Fic was significantly altered in both treated cell types as compared to WT. A strong negative correlation between fu,cell and PL content in the cell homogenates was observed, whereas the increased NL content in the NL+PL+ cells did not increase binding further. The importance of PLs for drug binding was confirmed by affinities to beads coated with purified PLs. The NL+PL+ cells lacked acidic subcellular compartments (i.e., endo-lysosomal space), which further influenced the subcellular distribution of cationic drugs. In conclusion, our results suggest that PL content, but not NL content, is a major determinant of drug binding in cells, and that PL beads may constitute a simple alternative to more cumbersome cell distribution studies.

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Polar-group behaviour in mixed monolayers of phospholipids and fusogenic lipids.

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