Phospholipid Bilayers as Molecular Models for Drug‐Cell Membrana Interactions.

Abstract

Since cell membranes are highly complex entities, there has been extensive interest in employing simple models to mimic biological cell membranes. Phospholipids are amphipatic molecules with long hydrophobic acyl chains and zwitterionic polar heads which are assembled into different types of molecular aggregates. The most relevant is the bilayer because of its relation with cell membranes. Among a large variety of relevant biological functions, the cell membrane acts as a diffusion barrier and protects the cell interior. Both structure and functions of the cell membrane are susceptible to alterations as a consequence of interactions with extrinsic chemical species such as therapeutic drugs. On the other hand, pharmacologic activity of a drug frequently involves an intial interaction with cell membranes even if they are not their final targets. With the aim to better understand the molecular mechanisms of the interaction of therapeutic drugs with cell membranes we utilize human erythrocyte membranes and molecular models of red blood cell membranes. Human erythrocytes are an ideal cell system for studying basic drug-membrane interactions, because they are composed of only one membrane and have no internal organelles. On the other hand, although less specialized than many other cell membranes, they carry on enough functions in common with them such as active and passive transport, and the production of ionic and electric gradients, to be considered representative of the plasma membrane in general. Molecular models of cell membranes consist of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) bilayers, representative of phospholipid classes located in the outer and inner monolayers of cell membranes, particularly of the human erythrocyte, respectively. The capacity of drugs to interact with membrane bilayers is currently evaluated in our labs by X-ray diffraction on DMPC and DMPE multilayers; DMPC large unilamellar vesicles (LUV) and isolated unsealed human erythrocyte membranes (IUM) are studied by fluorescence spectroscopy, and intact human erythrocytes are observed by scanning electron microscopy (SEM). We have been using these systems and techniques in order to determine the interaction with and the membraneperturbing effects of different compounds of therapeutic interest. As an example of our research, results obtained with the nonsteroidal anti-inflammatory drug diclofenac, the calcium channel blocker verapamil and the neuroleptic chlorpromazine will be presented. Acknowledgements FONDECYT (grant 1090041). L4.2