Drug-membrane interactions

Rooney, Eamonn Kiaran (1986) Drug-membrane interactions. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Initial investigation on the effects of a number of antihistamine drugs on the temperature of the gel to liquid-crystalline phase transition in phospholipid bilayers showed that charge effects on drug binding, largely ignored in previous studies, could be adequately described by application of the Gouy-Chapman theory of the electrical double layer. This work indicated that substantial surface potentials were developed as a result of drug binding, an effect that was directly confirmed by microelectrophoresis studies. The existence of such drug-induced surface potentials might be expected to have important consequences for the activities of membrane enzymes, particularly those dealing with ionic substrates or cofactors, e.g. the (Ca²⁺-Mg²⁺)- ATPase of muscle sarcoplasmic reticulum. Application of binding constants derived for the interaction of drugs with phospholipid bilayers showed that observed shifts in the apparent Ca²⁺ affinity of (Ca²⁺-Mg²⁺)-ATPase in the presence of hydrophobic amine drugs could be accounted for by electrostatic effects. In addition to their charge-related effects, hydrophobic drugs might be experienced to bind extensively to both the phospholipid bilayer and to hydrophobic regions of integral membrane proteins. This possibility was investigated both in model systems and in (Ca²⁺-Mg²⁺)-ATPase by use of a fluorescent probe as a model compound. The emission properties of the probe, dansyl benzocaine, are unusually sensitive to environment, enabling resolution of the separate contributions of protein-bound and lipid-bound probe to the fluorescence spectrum. Dansyl benzocaine was shown to bind to both lipid and protein elements of the (Ca²⁺-Mg²⁺)-ATPase membrane, with complex effects on enzyme activity. (D73654/87)

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