Glutathione reaction with cisplatin

Intracellular thiolate ligands such as glutathione (GSH, the tripeptide y-L-Glu-L-Cys-Gly) are believed to inactivate cisplatin because the reactions with cisplatin tend to be irreversible (35). Elevated levels of GSH have been observed in cisplatin-resistant cells. Recently, it has been shown that an MRP gene, which encodes a human ATP-dependent glutathione S-conjugate export pump (GS-X pump), is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells (36). The GS-X pump may contribute to the excretion of Pt-GS complexes from cells (37). 

Glutathione readily replaces the GSMe on platinum in the reaction with [Pt(dien)(GSMe)]2+ (GSMe = S-methylglutathione) - this system is claimed to be an effective model for cisplatin-protein interaction 224). Rate constants and activation parameters have been... 

Release of ammonia from cisplatin inside red cells in vitro on reaction with intracellular glutathione (GSH, 2 mM) can be detected by NMR studies on intact cells (28) initially, displacement of Cl occurs, giving cis-[Pt(SG)(Cl)(NH3)2], and finally a 1 2 Pt GSH polymer. The trans isomer reacts more rapidly, but forms the stable product trans-[Pt(SG)2(NH3)2l. 

In human plasma at 37°, the disappearance of cisplatin occurred with a tl/2 value of 1.3 h. Kinetics analysis demonstrated that the major components of reaction were formation of hydrated species (tl/2 3.4 h), irreversible binding to proteins (t1/2 2.1 h), and formation of mobile conjugates (e.g., with glutathione t1/2 24 h) [185], A very large quantity of relevant data are compiled in [181],... 

Transplatin reacts 360 times faster than cisplatin with glutathione [27], a reaction likely to remove platinum from the cell, through ATP-dependent efflux [28]. It has been shown that a thioether ligand on a platinum triamine complex can be slowly replaced by a guanine-N(7), suggesting a possible platinum transporter role for such thioether compounds towards DNA [6], (This topic is discussed in the contribution by J. Reedijk and J. M. Teuben.)... 

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