Glutathione interaction with cisplatin

The mechanisms of cisplatin-induced nephrotoxicity have not been fully elucidated. Like several nephrotoxic heavy metals (for example mercury), cisplatin can accumulate in the kidney, where it can interact with sulfhydryl compounds, resulting in increased membrane fragility and depletion of intracellular glutathione. There is some evidence that cisplatin can induce apoptosis and necrosis of kidney cells dose-dependently. In vitro studies have suggested that the constitutive expression of antiapoptotic proteins (for example bcl-X) might be inversely correlated with the sensitivity of renal tubular cells (146,195-197). 

Although DNA is generally accepted to be the critical cellular target for cisplatin, the drug undoubtedly interacts with other cellular components, especially those containing sulfhydryl groups. Glutathione mhibits... 

The diminution of antitumour activity by sulfur nucleophiles may be due to the sequestration of active metabolites or to interaction with Pt— DNA adducts. Some agents such as DDTC do not affect the antitumour activity of cisplatin [28], whereas other agents such as TU do so. Thiourea can remove Pt—DNA crosslinks and inhibits the cytotoxicity [29]. Indeed, thiourea has been of great utility in allowing examination of the mechanism of formation of Pt—DNA adducts (see Chapter 4.5). Depletion of intracellular glutathione (GSH) content, on the other hand, results in enhanced platinum cytotoxicity [30], and GSH can also quench Pt monoadducts [31]. Thus, all sulfur nucleophiles do not behave in the same manner with platinum complexes and the fundamental aspects of these interactions and their relationships to platinum complex metabolism are now being explored (Chapter 3.7). Some aspects of the biochemical mechanisms relating to these points are summarized in recent volumes [27,91]. 

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... 

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