Interaction of Biguanides with Mitochondrial and Synthetic Membranes.

Biguanides inhibit a large scale of metabolic processes which in most cases are membrane- linked. Oxidative phosphorylation is strongly inhibited in that part of the respiratory chain located on the substrate site of cytochrome c. It is assumed that inhibition is due to physical changes within the membrane phospholipids, rather than a result of direct interaction with functional intermediates of energy conservation. The following observations have been made. 1. Binding affinity to mitochondrial, submitochondrial and other membranes is identical with that to pure phospholipids. 2. Synthetic phospholipid vesicles exactly resemble the binding properties and kinetics of mitochondrial membranes. 3. Gradual lipid extraction of mitochondrial membranes causes a proportional decrease of binding capacity but no change of affinity constants. 4. The stoichiometry shows that the capacity for inhibitor binding is indeed in the range of mitochondrial phospholipid content. 5. Binding of the inhibitors occurs to the aqueous lipid interface of the membrane. Possibilities are discussed for the mode of action of the inhibitors representing firmly fixed positive charges.