Molecular mechanisms of gossypol action on lipid membranes.

Gossypol, an aldehyde extracted from cotton plants, produces both general toxic and antifertility effects in mammals. The cellular mechanisms by which gossypol exerts these effects are not understood. In this study, we have characterized the interactions of gossypol with lipid monolayer and bilayer membranes in order to assess if the drug acts by modifying the electrochemical properties of membranes. The charged form of gossypol binds to monolayers of different lipid compositions with apparent dissociation constants ranging from 0.7 to 2 microM. Binding of charged gossypol decreases the interfacial potential by 80-235 mV, the magnitude of this decrease being dependent upon the lipid composition. Gossypol also induces a conductance in phospholipid bilayer membranes. The relation between steady-state bilayer conductance versus gossypol concentration indicates that the current-carrying species is a single molecule of gossypol. The increase in bilayer conductance is accompanied by an increase in proton permeability. These changes induced by gossypol in model membranes can account for the mitochondrial uncoupling effects of this molecule and may be responsible for the inhibitory effects of gossypol on several membrane transport systems.