Effect of cis-, trans-diamminedichloroplatinum(II) and DBP on human serum albumin

Both isomers of diamminedichloroplatinum(II) bind to albumin and induce the formation of the albumin dimer (MW similar to 140 kDa). The trans isomer e xhibits a much greater tendency to induce a protein dimerization than the c is isomer. Under similar experimental conditions, the phosphonic derivative of diammineplatinum(II) (DBP) does not induce any dimer formation. The amo unt of bound complex per mol of human serum albumin (HSA, for an incubation time of 7 days) was found to be 6, 10.5 and 1 mol for cis-,trans-DDP and D BP, respectively. The relative fluorescence intensity of platinum-bound HSA decreases to about 55% for cis-DDP, 45% for trans-DDP and to 85% for DBP w hen compared to the complex-free protein, suggesting that the binding occur s in the proximity of the Trp214 residue. The structural studies (CD) have shown that only DDP-isomers cause the distinct modification of HSA native s tructure (alpha-helical content). Pt(II) complexes binding to HSA affect th e affinity of HSA towards heme and bilirubin. High excess of DDP prevents t he heme and bilirubin binding, while DBP affects this binding much less eff ectively due to the low amount of the protein-bound complex. Reactions of p latinum complexes with albumin are believed to play an important role in th e metabolism of this anticancer drug. The minor effect of DBP on HSA may in dicate that the toxicity of the phosphonate analog is much lower than toxic ities of DDP isomers, most likely due to kinetic reasons. (C) 1999 Elsevier Science Inc. All rights reserved.