| Abstract
| - 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and 17-allylamino-17-demethoxygeldanamycin (17-AAG) are two derivatives of geldanamycin (GA) that are currently undergoing clinicalevaluation as anticancer agents. These agents bind to heat shock protein 90 (hsp90), resulting in thedestabilization of client proteins and inhibition of tumor growth. In a search for the mechanism ofhepatotoxicity, which is a dose-limiting toxicity for these agents, we found that GA and its derivatives,17-AAG and 17-DMAG, react chemically (i.e., nonenzymatically) with glutathione (GSH). A combinationof liquid chromatography/electrospray ionization/mass spectrometry and nuclear magnetic resonanceanalyses were used to identify the product of this reaction as a GSH adduct in which the thiol group ofGSH is substituted in the 19-position of the benzoquinone ring. The reaction proceeds rapidly with GAand 17-DMAG (half-lives of approximately 1.5 and 36 min, respectively) and less rapidly with 17-AAGand its major metabolite, 17-AG (half-lives of approximately 9.8 and 16.7 h). The reaction occurs at pH7.0, 37 °C, and a physiological concentration of GSH, indicating that cellular GSH could play a role inmodulating the cellular toxicity of these agents and therefore be a factor in their mechanism of differentialtoxicity. Moreover, reactions with thiol groups of critical cellular proteins could be important to themechanism of toxicity with this class of anticancer agents.
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