CISPLATIN COMPLEXES WITH PHOSPHATIDYLSERINE IN MEMBRANES

Upon incubation of the anticancer drug cisplatin [cis-diamminedichloro platinum(II)] with model membranes composed of phosphatidylserine (PS) , a stable product is formed that has been isolated after chloroform/m ethanol extraction of the sample. The product formation is specific fo r PS and does not occur with other major membrane phospholipids. The r ate and extent of product formation is dependent on the pH, chloride i on concentration, and temperature, with the highest rate at pH 6.0, in the absence of Cl- and at 37 degrees C, indicating that positively ch arged aquated cisplatin is the reactive species. Over 80% of PS is con verted within 15 h under these conditions with a halftime of 5 h. PS c an be regenerated by an excess of glutathione. Mass spectrometry exper iments demonstrate that interaction of cisplatin with PS involves a lo ss of two chloride ions and coordination of platinum to the amine and carboxyl group of the serine moiety. Cisplatin forms complexes specifi cally with PS not only in model membranes but also in the plasma membr ane of human erythrocytes. Since PS is essential in several cellular p rocesses, its interaction with cisplatin may have important physiologi cal implications.