Interaction of serum albumin with anesthetics

The molecular mechanism of anesthesia is one of the long-standing unresolved problems in medical science. Although two representative theories of anesthesia, a protein receptor theory based on the direct binding of anesthetics to several signal receptor proteins in nerve membranes and a lipid membrane theory based on the indirect binding of anesthetics to nerve membranes with high content of lipids, have been argued up to now, the action mechanism has not yet been clarified. More recently, the emphasis has shifted from theories oflipid perturbation to the idea that anesthetics bind directly to specific proteins.Serum albumin is an abundant plasma protein transporting a wide variety of drugs and endogenous compounds and has been widely used for life-science studies. A number of studies on the binding of such drugs and compounds to serum albumin have been reported since pioneer works by Foster et al. in late 1950s. In the beginning of 1990s, Carter et al. determined the detailed molecular structure of serum albumin from the X-ray structural analysis, and subsequently the binding sites of several small ligands for serum albumin were identified on the structure. In such circumstances, serum albumin has been regarded a good model for anesthetic action, and the binding data of anesthetics to serum albumin examined by various physicochemical methods have been accumulated for the last several decades. Most of the binding studies of anesthetics to serum albumin showed that there exist weak but specific interactions between serum albumin and anesthetics, and crystallographic data suggested that all anesthetics bind fatty-acid binding sites on serum albumin without binding the unique site to each anesthetic. On the other hand, a comparative study of ligand interactions indicated that the binding mode of anesthetics is pronouncedly different from that of specific binders such as fatty acids. Here model studies of anesthetic action by using serum albumin are reviewed, and characteristic binding modes of anesthetics to serum albumin are elucidated in connection with the anesthetic mechanism.