Phospholipid bilayers as biological membrane models: The effect of N,N′-bis(dichloroacetyl)-1,12-diaminododecane

Abstract

N,N′-bis(dichloroacetyl)-1,12-diaminododecane is a potent inhibitor of microsomal drug metabolism and also uncouples succinate-linked mitochondrial oxidative phosphorylation, apparently by promoting a transient permeability to anions. When added in very small concentrations to synthetic phospholipid bilayers made from a 1∶4∶4 mixture of purified cardiolipin, phosphatidylcholine, and phosphatidylethanolamine, the drug causes a rapid, transient decrease in electrical resistance with a return to an end-resistance somewhat lower than the initial one. The magnitude of the decrease was related to drug concentration. However, the drug produced a nontransitory, i.e. permanent decrease in resistance of bilayers made from pure phosphatidylcholine or cardiolipin. The 1∶4∶4 mixture of lipids, which closely resembles the lipid composition of the inner mitochondrial membrane yielded drug effects most closely resembling those observed in intact mitochondria. Transference number measurements on the 1∶4∶4 bilayer with an impressed KCl gradient revealed that the drug-induced decrease in electrical resistance was caused by an increase in the fraction of current carried by the anions in the system. The 1∶4∶4 phospholipid bilayer thus mimics the mitochondrial inner membrane in its response to this drug and indicates that the lipid composition of the lipid bilayer is a major determinant of at least some of its physical characteristics. The effect of varying the structure of the drug was also examined.