Glutathione readily replaces the thioether on platinum in the reaction with [Pt(dien)(GSMe)](2+) (GSMe = S-methylated glutathione); a model study forcisplatin-protein interactions

As models for cis-[PtCl2(NH3)(2)] (cisplatin)-protein interactions, the rea ctions of [Pt(dien)Cl](-) with the tripeptides GSMe (S-methylated glutathio ne) and GSH (glutathione, gamma-glutamylcysteinylglycine) have been studied . The substitution reaction of the platinum-methionine model adduct [Pt(die n)(GSMe)](2+) with GSH has been investigated using H-1 and Pt-195 NMR. It w as found that GSH substitutes GSMe in [Pt(dien)(GSMe)](2+), readily forming [{Pt(dien)}(2)GS](3+). At pD greater than or equal to 7.0 the intermediate [Pt(dien)(GS)](+) was observed. Kinetic and thermodynamic parameters of th is reaction were determined at pD 3.2: k=1.1x10(-3) M-1 s(-1), t(1/2)=24.7 h, Delta H double dagger=1.5 +/- 0.3 kJ mol(-1), Delta S double dagger=5 +/ - 1 J K-1 mol(-1) at 298 K; and k=28.5x10(-3) M-1 s(-1), t(1/2)=0.97 h, Del ta H double dagger=1.5 +/- 0.3 kJ mol(-1), Delta S double dagger=4 +/- 1 J K-1 mol(-1) at 316 K. At alkaline pH the substitution reaction occurs withi n 5 min, illustrating the dramatic influence of the pH on this reaction. Th ese parameters are discussed in relation to the competition between GSMe an d the N7 atom of guanosine monophosphate. The intermolecular substitution o f GSMe by GSH is much faster than the substitution by guanine N7, even unde r acidic conditions. This platinum-thioether to -thiolate substitution can play a significant role in the cellular processing of platinum-protein addu cts, and is an important mechanism in the circumvention of cisplatin induce d toxicity by thiol-containing protective agents.